1-benzyl-1,3-dihydroindol-2-one derivatives, their preparation and the pharmaceutical compositions in which they are present

ABSTRACT

The present invention relates to 1-benzyl-1,3-dihydroindol-2-one derivatives of the formula ##STR1## to their preparation and to the pharmaceutical compositions in which they are present. These derivatives have an affinity for the vasopressin and oxytocin receptors.

This application is a division of application Ser. No. 08/282,644, filedJul. 29, 1994, now U.S. Pat. No. 5,618,833.

The present invention relates to 1-benzyl-1,3-dihydroindol-2-onederivatives, to their preparation and to the pharmaceutical compositionsin which they are present.

Several patents or patent applications describe1-benzyl-1,3-dihydroindol-2-one derivatives.

Patent application JP-87/227987 describes the preparation of theoxothiolan derivative of the formula ##STR2##

Patent applications EP 28906 and EP 66378 describe compounds of theformula ##STR3## in which R' can be a CH₂ Ph group, more particularly3,4-Cl₂ C₆ H₃ CH₂. These compounds lower the sorbitol level in thesciatic nerve.

U.S. Pat. No. 4,226,860 describes compounds of the formula ##STR4## inwhich: R" is an alkyl or a carboxyalkyl,

R"₁ is an alkyl,

R"₂ is an alkyl or phenylalkyl, and

X is a methylene or an oxygen.

These compounds are useful for the treatment of hypertension.

Patent DE 3529994 describes compounds of the formula ##STR5## in whicheach of the 3 phenyl rings can carry a variety of substituents. Thesecompounds are calcium antagonists.

Patent application EP 344634 describes indolone or quinolone derivativesof the formula ##STR6## in which: n=0 or 1,

A and B are hydrogen, an alkyl, an alkenyl, an alkynyl, a benzyl or acycloalkyl, and

R"'₁ and R"'₂ independently are an alkyl, an alkenyl or a cycloalkyl, orR"'₁ and R"'₂ together are a C₃ -C₇ -cycloalkane.

These compounds are platelet aggregation inhibitors.

U.S. Pat. No. 4,806,651 describes the preparation of compounds of theformula ##STR7## in which: Het₁ and Het₂ are heterocycles,

R can be a substituted phenyl, and

p is zero or one.

These compounds are useful for the treatment of cognitive orneurological dysfunctions.

Several patent applications have recently described families ofcompounds of non-peptide structure which are active on the vasopressinand/or oxytocin receptors. The following may be mentioned: patentapplications EP 382 185, EP 444 945 and EP 514 667, EP 469 984, EP 526348 and EP 581 939, patent applications WO 91/05 549 and WO 93/15 051and, more particularly, patent application JP-03/127732. The latterdescribes indole-3-propionic acid derivatives of the formula ##STR8## inwhich: R""₁ is hydrogen, an alkyl, an alkenyl, a phenylalkyl, atetrahydrofuryl, an alkoxycarbonyl, an alkoxycarbonylalkyl, acarboxyalkyl or an alkanoyl;

R""₂ is hydrogen, a hydroxyl, an alkoxy, an alkyl, a phenylalkyl, aphenylalkoxy or a halogen;

R""₃ is a hydrogen, an alkoxy, a free or substituted amino group or anamino acid residue;

R""₄ is hydrogen, an alkyl or a phenylalkyl; and

R""₅ is a benzoyl, a phenyl, an alkyl, a phenylalkenylcarbonyl, athienylcarbonyl, a phenylsulfonyl, a pyridylcarbonyl or animidazolylcarbonyl, it being possible for the phenyl and alkyl groups ofthe substituent R""₅ to be substituted.

These compounds are vasopressin antagonists.

U.S. Pat. No. 4,803,217 claims hapalindolinones obtained byfermentation, which are vasopressin antagonists. These compounds arerepresented by the following formula: ##STR9## in which R is H or Cl.

The 1-benzyl-1,3-dihydroindol-2-one derivatives according to the presentinvention have an affinity for the vasopressin and oxytocin receptors.

Vasopressin is a hormone known for its antidiuretic effect and itseffect in the regulation of arterial pressure. It stimulates severaltypes of receptors, namely V₁ (V_(1a), V_(1b)) and V₂. These receptorsare localized in the liver, vessels (coronary, renal, cerebral),platelets, kidney, uterus, adrenal glands, central nervous system andpituitary gland. Oxytocin has a peptide structure similar to that ofvasopressin. The oxytocin receptors are also found on the smooth muscleof the uterus, as well as on myoepithelial cells of the mammary gland,in the central nervous system and in the kidney. The localization of thedifferent receptors is described in: S. JARS et al., Vasopressin andoxytocin receptors: an overview, in Progress in Endocrinology; H. IMURAand K. SHIZURNE ed., Experta Medica, Amsterdam, 1988, 1183-1188, and inthe following articles: Presse Medicale, 1987, 16 (10), 481-485; J. Lab.Clin. Med., 1989, 114 (6), 617-632; and Pharmacol. Rev., 1991, 43 (1),73-108. Vasopressin thus exerts cardiovascular, hepatic, antidiureticand aggregating effects and effects on the central and peripheralnervous system and in the uterine domain. Oxytocin is involved inparturition, lactation and sexual behavior.

The compounds according to the present invention make it possibleselectively either to mimic the effects of the hormone (in the case ofagonists) or to inhibit them (in the case of antagonists). Vasopressinreceptor antagonists can affect the regulation of the central andperipheral circulation, especially the coronary, renal and gastriccirculation, as well as the regulation of hydration and the release ofadrenocorticotrophic hormone (ACTH). Vasopressin agonists canadvantageously replace vasopressin or its analogs in the treatment ofdiabetes insipidus; they can also be used in the treatment of enuresisand in the regulation of hemostasis: treatment of hemophilia and vonWillebrand's syndrome, antidote to platelet aggregating agents, F. A.LASZLO, Pharmacol. Rev., 1991, 43, 73-108; and Drug Investigation, 1990,2 (Suppl. 5), 1-47. The hormones themselves, namely vasopressin andoxytocin, and some of their peptide or non-peptide analogs are used intherapeutics and have been found to be effective. Several reviews andnumerous literature articles may be mentioned: Vasopressin, P. GROSS etal. ed., John Libbey Eurotext, 1993, in particular 243-257 and 549-562;F. A. LASZLO and F. A. LASZLO Jr., Clinical perspectives for vasopressinantagonists, Drug News Perspect., 1993, 6 (8); W. G. NORTH, J. Clin.Endocrinol., 1991, 73, 1316-1320; J. J. LEGROS et al., Prog.Neuro-Pharmacol. Biol. Psychiat., 1988, 12, 571-586; K. E. ANDERSSON etal., Drugs Today, 1988, 24 (7), 509-528; D. L. STUMP et al., Drugs,1990, 39, 38-53; S. CALTABIANO et al., Drugs Future, 1988, 13, 25-30; Y.MURA et al., Clin. Nephrol., 1993, 40, 60-61; and FASEB J., 1994, 8 (5),A 587:3398.

Thus the compounds according to the invention are useful especially inthe treatment of complaints of the central and peripheral nervoussystem, the cardiovascular system, the renal domain and the gastricdomain and in disorders of sexual behavior, in man and animals.

The present invention relates to compounds of the formula ##STR10## inwhich: R₁ and R₂ are each independently a hydrogen; a halogeno; ahydroxyl; an ω-halogeno(C₁ -C₇)alkoxy; a (C₁ -C₇)alkyl; atrifluoromethyl; a (C₁ -C₇)alkoxy; a polyhalogeno(C₁ -C₇)alkoxy; anω-hydroxy(C₂ -C₇)alkoxy; an ω-methoxy(C₂ -C₇)alkoxy; an ω-amino(C₂-C₇)alkoxy which is free or substituted by one or two (C₁ -C₇)alkyls; a(C₃ -C₇)cycloalkoxy; a (C₃ -C₇)cycloalkylmethoxy; a phenoxy; abenzyloxy; a (C₁ -C₇)alkylthio; a phenylthio; a nitro; an amino which isfree or substituted by one or two (C₁ -C₇)alkyls; a cyano; a formyl; a(C₁ -C₇)alkylcarbonyl; a benzoyl; a formyloxy; a (C₁-C₇)alkylcarbonyloxy; a benzoyloxy; a (C₁ -C₇)alkylsulfonamido; aphenylsulfonamido; a benzylsulfonamido; a (C₁ -C₇)alkylcarbonylamino; a(C₁ -C₇)alkoxycarbonylamino; a ureido which is unsubstituted orsubstituted by a phenyl, a benzyl or one or two (C₁ -C₇)alkyls; or athioureido which is unsubstituted or substituted by a phenyl, a benzylor one or two (C₁ -C₇)alkyls, with the proviso that R₁ and R₂ are notsimultaneously hydrogen;

R₃ and R₄ together form a group --(CH₂)_(p) X(CH₂)_(q) --; or

R₃ and R₄, together with the carbon to which they are bonded, form anoptionally fused, saturated or unsaturated C₃ -C₁₂ hydrocarbon ringwhich is unsubstituted or substituted by one or more (C₁ -C₇)alkylgroups, by a C₃ --C₅ -spirocycloalkyl, by an oxo group or by one or twohydroxyls which are free or substituted by a group selected from thefollowing: (C₁ -C₄)alkyl, (C₁ -C₂)alkoxy(C₁ -C₄)alkyl, phenyl(C₁-C₂)alkoxy(C₁ -C₄)alkyl, tetrahydrofuranyl and tetrahydropyranyl;

R₅ is hydrogen or has one of the meanings designated for R₆ ;

R₆ is a halogen; a (C₁ -C₇)alkyl; a trifluoromethyl; a cyano; a nitro; ahydroxylamino; a hydroxyl; a carboxyl; a guanidino which isunsubstituted or substituted in the 1-position by a (C₁ -C₇)alkyl and/orin the 3-position by one or two (C₁ -C₇)alkyls, a phenyl or a benzyland/or in the 2-position by a cyano; a group --OR₇ ; a group --SR₇ ; aformyl; a (C₁ -C₇)alkylcarbonyl; a benzoyl; a (C₁ -C₇)alkoxycarbonyl; aphenoxycarbonyl; a benzyloxycarbonyl; a group --CONR₁₇ R₁₈ ; a group--CSNR₁₁ R₁₉ ; a group --SO₂ NR₂₀ R₂₁ ; a (C₁ -C₇)alkylsulfonamido; agroup --NHSO₂ --Ar; a benzylsulfonamido; an aminosulfonamido in whichthe amino is free or substituted by R₁₆ and R₂₂ ; a group --NR₈ R₉ ; agroup --CO--NH--CR₁₀ R₂₃ --COR₁₂ ; or a group --CH₂ NR₈ R₉ ;

R₇ is a (C₁ -C₇)alkyl; a phenyl; a benzyl; a (C₃ -C₇)cycloalkyl; a (C₂-C₇)alkenyl; an ω-halogeno(C₂ -C₇)alkyl; a polyhalogeno(C₁ -C₇)alkyl; anω-hydroxy(C₂ -C₇)alkyl; a formyl; a (C₁ -C₇)alkylcarbonyl; a benzoyl; anω-carboxy(C₁ -C₇)alkyl; an ω-(C₁ -C₇)alkoxycarbonyl(C₁ -C₇)alkyl; anω-benzyloxycarbonyl(C₁ -C₇)alkyl; an ω-amino(C₂ -C₇)alkyl in which theamino group is free or substituted by one or two (C₁ -C₇)alkyls, or inthe form of an ammonium ion; or an ω-carbamoyl(C₁ -C₇)alkyl in which thecarbamoyl is free or substituted by one or two (C₁ -C₇)alkyls;

R₈ and R₉ are each independently a hydrogen; a (C₁ -C₇)alkyl; or a group--CH₂ --Ar; R₉ can also be a group Ar; a (C₃ -C₈)alkenyl; a formyl; a(C₁ -C₇)alkyl carbonyl; a (C₁ -C₇)alkylthiocarbonyl; a (C₃-C₇)cycloalkylcarbonyl; a (C₃ -C₇)cycloalkylthiocarbonyl; an ω-amino(C₂-C₇)alkylcarbonyl in which the amino is free or substituted by one ortwo (C₁ -C₇)alkyls; an ω-hydroxy(C₁ -C₇)alkylcarbonyl; an ω-benzyloxy(C₁-C₇)alkylcarbonyl; a pyridylcarbonyl; a methylpyridylcarbonyl;thienylcarbonyl; a group --CO--Ar; a group --CO--CH₂ --Ar; (C₁-C₇)alkoxycarbonyl; a phenoxycarbonyl; a phenoxythiocarbonyl; abenzyloxycarbonyl; a group --CO--CR₁₀ R₂₃ --NR₁₁ R₁₉ ; a group --CR₁₀R₂₃ COR₁₂ ; a group --(CH₂)_(t) COR₁₂ ; a group --CO(CH₂)_(u) COR₁₂ ; agroup --CONR₁₄ R₂₄ ; a group --CSNR₁₄ R₂₄ ; or a heterocyclic radicalselected from pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl and thiazolyl;

or else R₈ and R₉, together with the nitrogen atom to which they arebonded, form hydantoin; N-methylhydantoin; or a heterocyclic radicalselected from pyrrol-1-yl, Δ3-pyrrolin-1-yl, pyrrolidin-1-ylisoindolin-2-yl in which the benzene ring unsubstituted or substitutedby a halogen, a (C₁ -C₇)alkyl, a trifluoromethyl or a methoxy;

R₁₀ and R₂₃ are each independently hydrogen; a (C₁ -C₇)alkyl; or abenzyl;

or R₁₀ and R₂₃, together with the carbon atom to which they are bonded,form a (C₃ -C₇)cycloalkyl;

R₁₁ and R₁₉ are each independently hydrogen; or a (C₁ -C₇)alkyl;

R₁₂ is a hydroxyl; a (C₁ -C₇)alkoxy; or an amino which is free orsubstituted by one or two (C₁ -C₇)alkyls;

R₁₃ is hydrogen; a (C₁ -C₇)alkyl; a phenyl; a benzyl; a formyl; a (C₁-C₇)alkylcarbonyl; a benzoyl; a (C₁ -C₇)alkoxycarbonyl; or a carbamoylwhich is unsubstituted or substituted by one or two (C₁ -C₇)alkyls;

R₁₄ and R₂₄ are each independently hydrogen; or a (C₁ -C₇)alkyl; R₂₄ canalso be a (C₁ -C₇)alkyl substituted by R₁₅ ; a group Ar; a (C₃-C₇)cycloalkyl; or an adamantyl;

or R₁₄ and R₂₄, together with the nitrogen atom to which they arebonded, form a heterocycle selected from morpholine, thiomorpholine,piperazine, azetidine, pyrrolidine, piperidine and perhydroazepine, saidheterocycle being unsubstituted or substituted by one or more methylgroups, a phenyl or an amino group which is free or carries a protectinggroup;

R₁₅ is a group Ar; a pyridyl; a hydroxyl; a (C₁ -C₇)alkoxy; a group--NR₁₁ R₁₉ ; a carboxyl; or a (C₁ -C₇)alkoxycarbonyl;

R₁₆ and R₂₂ are each independently a hydrogen; or a (C₁ -C₇)alkyl;

or R₁₆ and R₂₂, together with the nitrogen aton to which they arebonded, form a heterocycle selected from azetidine, pyrrolidine,piperidine, piperazine and perhydroazepine, said heterocycle beingunsubstituted or substituted by one or more methyl groups;

R₁₇ and R₁₈ are each independently hydrogen; or a (C₁ -C₈)alkyl; R₁₈ canalso be a (C₃ -C₇)cycloalkyl which is unsubstituted or substituted by a(C₁ -C₄)alkyl; a group Ar; a pyridyl; a methylpyridyl; a piperid-4-ylsubstituted in the 1-position by R₂₇ ; a piperid-1-yl; apyrrolidin-1-yl; a morpholin-4-yl; or a (C₁ -C₇)alkyl substituted by oneor more halogens or by R₂₆ ;

or else R₁₇ and R₁₈, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₂₅ ;

R₂₀ and R₂₁ are each independently hydrogen; or a (C₁ -C₇)alkyl;

or else R₂₀ and R₂₁, together with the nitrogen atom to which they arebonded, form a heterocyclic radical R₂₅ ;

R₂₅ is a morpholin-4-yl; a thiomorpholin-4-yl; an azetidin-1-yl which isunsubstituted or substituted in the 3-position by a group -NR₁₁ R₁₉, a(C₁ -C₇)alkyl, a phenyl, a benzyl, or a (C₁ -C₇)alkylcarbonyl; aperhydroazepin-1-yl; a piperazin-1-yl which is unsubstituted orsubstituted in the 4-position by a (C₁ -C₇)alkyl, a phenyl, a benzyl, a(C₁ -C₇)alkylcarbonyl, a (C₁ -C₇)alkoxycarbonyl or a benzyloxycarbonyl;a piperid-1-yl which is unsubstituted or substituted in the 4-positionby a (C₁ -C₇)alkyl, a phenyl, a benzyl, a (C₁ -C₇)alkylcarbonyl or agroup --NR₁₁ R₁₉ ; or a pyrrolidin-1-yl which is unsubstituted orsubstituted by a (C₁ -C₇)alkyl, a phenyl, a benzyl, a (C₁-C₇)alkylcarbonyl, a hydroxymethyl, a carboxyl, a (C₁ -C₇)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two (C₁-C₇)alkyls;

R₂₆ is a hydroxyl; a (C₁ -C₇)alkoxy; a cyano; a carboxyl; a (C₁-C₇)alkoxycarbonyl; a benzyloxycarbonyl; a group --NR₁₁ R₁₉ ; acarbamoyl which is free or substituted by one or two (C₁ -C₇)alkyls; apyrrolidin-1-ylcarbonyl; a piperid-1-ylcarbonyl; aperhydroazepin-1-ylcarbonyl; a group Ar; a (C₃ -C₇)cycloalkyl; anadamantyl; or a heterocyclic radical selected from a pyridyl, amethylpyridyl, a furanyl, a tetrahydrofuranyl, a thienyl, amethylthienyl, a pyrrolidin-1-yl, a piperid-1-yl and aperhydroazepin-1-yl;

R₂₇ is a hydrogen; a (C₁ -C₇)alkyl; a phenyl; a benzyl; a formyl; a (C₁-C₇)alkylcarbonyl; a benzoyl; a (C₁ -C₇)alkoxycarbonyl; aphenoxycarbonyl; or a carbamoyl which is free or substituted by one ortwo (C₁ -C₇)alkyls;

Ar is a phenyl which is unsubstituted or monosubstituted orpolysubstituted by a substituent selected from a halogen atom, a (C₁-C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁ -C₇)alkoxy, a carboxyl,a (C₁ -C₇)alkoxycarbonyl, a (C₁ -C₇)alkylcarbonyloxy, a nitro, a cyano,an amino, a (C₁ -C₇)alkylamino and a (C₁ -C₇)dialkylamino, saidsubstituents being identical or different;

m is 1 or, if R₆ is a halogen, a (C₁ -C₇)alkyl or a (C₁ -C₇)alkoxy, mcan also be 2, 3 or 4, or else (R₆)_(m) can be m substituents havingdifferent meanings selected from halogen, (C₁ -C₇)alkyl and (C₁-C₇)alkoxy;

p and q are each an integer, it being possible for their sum to varyfrom 3 to 6;

t is an integer which can vary from 2 to 5;

u is an integer which can vary from 0 to 3;

X is oxygen, a group --NR₁₃, a group --N(O)R₁₃ or a group S(O)_(x) ; and

x is 0, 1 or 2;

and their salts where appropriate.

If a compound according to the invention has one or more asymmetriccarbons, the invention includes all the optical isomers of thiscompound.

The salts of the compounds of formula (I) according to the presentinvention include those with mineral or organic acids which permit asuitable separation or crystallization of the compounds of formula (I),such as picric acid, oxalic acid or an optically active acid, forexample a mandelic acid or a camphosulfonic acid, and mineral or organicacids which form physiologically acceptable salts such as thehydrochloride, hydrobromide, sulfate, hydrogensulfate,dihydrogenphosphate, maleate, fumarate and naphthalene-2-sulfonate.

The salts of the compounds of formula (I) also include those withorganic or mineral bases, for example the salts with alkali metals oralkaline earth metals, such as the sodium, potassium and calcium salts,the sodium and potassium salts being preferred, or with an amine such astrometamol, or else those with arginine, lysine or any physiologicallyacceptable amine.

According to the present invention, halogen is understood as meaning anatom selected from fluorine, chlorine, bromine and iodine, preferablyfluorine or chlorine.

According to the present invention, amino-protecting group is understoodas meaning a group such as a (C₁ -C₄)alkyl, for example a methyl or atert-butyl; a benzyl; a substituted benzyl such as p-nitrobenzyl,p-chlorobenzyl or p-methoxybenzyl; a benzhydryl; a trityl; a benzoyl; a(C₁ -C₄)alkylcarbonyl, for example an acetyl; a (C₁ -C₄)alkoxycarbonyl,for example a methoxycarbonyl, an ethoxycarbonyl or atert-butoxycarbonyl; or a benzyloxycarbonyl.

According to the present invention, C₁ -C₇ -, C₁ -C₈ - or C₁ -C₄ -alkylis understood as meaning a linear or branched C₁ -C₇ -, C₁ -C₈ - or C₁-C₄ -alkyl. C₁ -C₇ - or C₁ -C₄ -alkoxy is understood as meaning a linearor branched C₁ -C₇ - or C₁ -C₄ -alkoxy.

According to the present invention, optionally fused, saturated orunsaturated C₃ -C₁₂ hydrocarbon ring is understood as meaning a varietyof hydrocarbon rings of monocyclic, bicyclic or tricyclic structure, forexample a cyclobutane, a cyclopentane, a cyclohexane, a cycloheptane, acyclooctane, an indane, a hexahydroindane, an adamantane, a norbornane,a norbornene, a dihydrophenalene, a tricyclo 5.2.1.0²,6 !decane or atricyclo 5.2.1.0²,6 !dec-8-ene, a bicyclo 2.2.1!heptane or a bicyclo3.3.1!nonane.

The compounds of formula (I) in which R₁ is in the 5-position of the1,3-dihydroindol-2-one and R₂ is hydrogen are preferred compounds.

The compounds of formula (I) in which R₁ is a chlorine or fluorine atomor an ethoxy group in the 5-position of the 1,3-dihydroindol-2-one andR₂ is hydrogen are preferred compounds.

The compounds of formula (I) in which R₃ and R₄, together with thecarbon to which they are bonded, form a C₃ -C₁₂ hydrocarbon ring arepreferred compounds; particularly preferred compounds are those in whichR₃ and R₄, together with the carbon to which they are bonded, form acycloheptane, an adamantane, a tricyclo 5.2.1.0²,6 !dec-8-ene, atricyclo 5.2.1.0²,6 !decane, a bicyclo 2.2.1!heptane, a bicyclo3.3.1!nonane or a cyclohexane which is unsubstituted or substituted by aC₃ -C₅ -spirocycloalkyl, by one or two C₁ -C₇ -alkyl groups or by a C₁-C₄ -alkoxy.

Very particularly preferred compounds of formula (I) are those in whichR₃ and R₄, together with the carbon to which they are bonded, form atricyclo 5.2.1.0²,6 !decane or a tricyclo 5.2.1.0²,6 !dec-8-ene.

The compounds of formula (I) in which R₃ and R₄, together with thecarbon to which they are bonded, form a piperidine-4 ring which isunsubstituted or substituted on the nitrogen by a C₁ -C₇ -alkyl are alsopreferred.

The compounds of formula (I) in which R₅ is either hydrogen or a methoxygroup in the 2-position and R₆ in the 4-position is a group --NR₈ R₉ inwhich R₈ and R₉ are as hereinabove defined are also preferred compoundsof the invention.

Particularly preferred are the compounds of formula (I) in which R₅ iseither hydrogen or a methoxy group in the 2-position and R₆ in the4-position is a methoxy, a (C₁ -C₇)alkylcarboxamido, a group --NHCO--Ar,a group --CONR₁₇ R₁₈ or a group --NR₈ CONR₁₄ R₂₄, in which thesubstituents Ar, R₁₇, R₁₈, R₈, R₁₄ and R₂₄ are as defined above for thecompounds of formula (I).

The following abbreviations are used in the description and in theExamples:

DCM: dichloromethane

ether: ethyl ether

iso ether: isopropyl ether

Boc: tert-butoxycarbonyl

Me, MeO: methyl, methoxy

Et, OEt: ethyl, ethoxy

Pr, iPr, nPr: propyl, isopropyl, n-propyl

Bu, iBu, tBu: butyl, isobutyl, tert-butyl

Ts: tosyl

Ph: phenyl

Bz: benzyl

Ac: acetyl

AcOEt: ethyl acetate

AcOH: acetic acid

MeOH: methanol

EtOH: ethanol

DMF: dimethylformamide

THF: tetrahydrofuran

DMSO: dimethyl sulfoxide

DIPEA: diisopropylethylamine

TEA: triethylamine

TFA: trifluoroacetic acid

TMEDA: tetramethylethylenediamine

BOP: benzotriazol-1-yloxytris(dimethylaminophosphonium)hexafluorophosphate

Lawesson's reagent:2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide

M.p.: melting point

saline solution: water saturated with sodium chloride

TLC: thin layer chromatography

HPLC: high pressure liquid chromatography

aqueous hydrochloric acid: dilute hydrochloric acid, about 1N

RT: room temperature

The present invention further relates to a process for the preparationof the compounds according to the invention, which comprises:

a) reacting a benzyl halide of the formula: ##STR11## in which Hal is ahalogen atom, preferably bromine or chlorine, and R'₅ and R'₆ arerespectively either R₅ and R₆ as defined above for (I), or precursorgroups of R₅ and R₆, with a 1,3-dihydroindol-2-one disubstituted in the3-position of the formula: ##STR12## in which R'₁ and R'₂ arerespectively either R₁ and R₂ as defined for (I), or precursor groups ofR₁ and R₂, and R₃ and R₄ are as defined above for (I); and

b) either, if R'₁ =R₁, R'₂ =R₂, R'₅ =R₅ and R'₆ =R₆, isolating theresulting compound of formula (I);

c) or, if any one of the groups R'₁, R'₂, R'₅ and/or R'₆ is respectivelya precursor group of R₁, R₂, R₅ and/or R₆, subjecting the compoundobtained in step a), hereafter called compound (I'), to a subsequenttreatment in order to prepare the compound of formula (I) by convertingany one of the groups R'₁, R'₂, R'₅ and/or R'₆ to R₁, R₂, R₅ and/or R₆respectively.

The reaction of step a) is carried out in an anhydrous solvent such asDMF or THF, in the presence of a metal hydride such as, for example,sodium hydride, or in the presence of an alcoholate such as potassiumtert-butylate.

The 1,3-dihydroindol-2-ones (II) are known or can be prepared by knownmethods according to different procedures.

Compounds (II) in which R'₁ and/or R'₂ are a halogen and R₃ and R₄,together with the carbon to which they are bonded, form aspirocyclobutane, a spirocyclohexane or a spirocycloheptane are known,for example from D. W. Robertson et al., J. Med. Chem., 1987, 30 (5),824-829. Furthermore, 5-chloro-3-spirocyclopentaneindol-2-one isdescribed in U.S. Pat. No. 3,947,451.

To prepare the compounds (II) in the case where R₃ and R₄ together are ahydrocarbon group, it is possible to use Brunner's reaction described byR. F. Moore and S. G. P. Plant in J. Chem. Soc., 1951, 3475-3478, whichleads to the preparation of compounds (II) in which CR₃ R₄ is acyclopentane or a cyclohexane.

This reaction is carried out by cyclizing a phenylhydrazide derivativeof the formula: ##STR13## in which R'₁ and R'₂ are as defined above for(II) and R₃ and R₄ are as defined above for (I), for example by heatingin quinoline in the presence of calcium oxide.

According to the same authors, the phenylhydrazide derivative (IV) isobtained by reacting a hydrazine derivative of the formula: ##STR14## inwhich R'₁ and R'₂ are as defined above for (II), with an acid halide ofthe formula: ##STR15## in which R₃ and R₄ are as defined above for (I).

In one particular embodiment, if R₃ and R₄, together with the carbon towhich they are bonded, form a polycondensed hydrocarbon ring, forexample a norbornane or a norbornene, the method described by J. Wolffet al., Tetrahedron, 1986, 42 (15), 4267-4272, is used: First of all alithium salt of the compound (IV) is prepared by reaction with a lithiumreagent such as n-butyllithium, in an inert solvent such as THF, at lowtemperature, and said salt is then cyclized by heating in a solvent suchas naphthalene or prehnitene (1,2,3,4-tetramethylbenzene).

The compounds (II) in which R'₁ =R'₂ =H and CR₃ R₄ is adamantane aredescribed by I. Fleming et al., J. Chem. Soc., Perkin Trans. I, 1991, 3,617-626. The compounds (II) in which R₃ and R₄, together with the carbonatom to which they are bonded, form an adamantane and R'₁ and R'₂ areother than hydrogen can be prepared by the method described above.

The hydrazine derivatives (V) are known or prepared by known methods.The same applies to the acid halides (VI).

A 1,3-dihydroindol-2-one disubstituted in the 3-position (II) can alsobe prepared from a 1,3-dihydroindol-2-one of the formula: ##STR16## inwhich R'₁ and R'₂ are as defined above for (II), by using variousprocesses.

For example, the addition of an alkylating agent is effected in anappropriate solvent by the method described by A. S. Kende and J. C.Hodges in Synth. Commun., 1982, 12 (1), 1-10. Thus, to prepare acompound (II) in which R₃ and R₄ together form a group of the formula--(CH₂)_(n) --, where n varies from 3 to 12, the reagent used is acompound of the formula Z(CH₂)_(n) Z, in which Z is an electrophilicgroup such as a halogen, preferably bromine or iodine, a tosyloxy groupor a mesyloxy group.

The compounds (II) in which R₃ and R₄, together with the carbon to whichthey are bonded, form a C₄ -C₈ hydrocarbon ring substituted by one ormore C₁ -C₇ -alkyl groups or by a C₃ -C₅ -spirocycloalkyl are preparedin the same way.

If R₃ and R₄ together form a group --(CH₂)_(p) X(CH₂)_(q) --, in whichp, q and X are as defined above for (I), a 1,3-dihydroindol-2-onedisubstituted in the 3-position of formula (II) can be prepared from a1,3-dihydroindol-2-one unsubstituted in the 3-position (VII) by reactionwith a compound of the formula

    Z--(CH.sub.2).sub.p --X--(CH.sub.2).sub.q --Z              (VIII)

in which Z is as defined above and X, p and q are as defined above for(I). The reaction is carried out in the presence of an alcoholate, forexample potassium tert-butylate, in an anhydrous solvent such as, forexample, THF.

If X is a nitrogen atom substituted by a formyl, a (C₁-C₇)alkylcarbonyl, a benzoyl, a (C₁ -C₇)alkoxycarbonyl or an N-(C₁-C₇)alkylcarbamoyl, the substitution on X can be effected either on the1,3-dihydroindol-2-one derivative (II) or on the final compound (I)starting from a compound in which the nitrogen atom (X═NH) isunsubstituted.

Thus, if X is a nitrogen atom substituted by a (C₁ -C₇)alkoxycarbonyl,the first step is to prepare a compound (II) or (I) in which X is NH,which is then reacted with the appropriate chloroformate to give thedesired compound (II) or (I). In the same way, a C₁ -C₇ -alkylisocyanate is reacted with a compound (II) or (I) in which X═NH to givea derivative (II) or a compound (I) in which X is a nitrogen atomsubstituted by an N-(C₁ -C₇)alkylcarbamoyl. The formic acid in thepresence of acetic anhydride or respectively an acid chloride or ananhydride is reacted with a compound (II) or a compound (I) in whichX═NH in order to prepare a compound of formula (II) or respectively acompound of formula (I) in which X is a nitrogen atom substituted by aformyl, a (C₁ -C₇)alkylcarbonyl or a benzoyl.

If X is a sulfur atom or a nitrogen atom substituted by R₁₃, it is alsopossible firstly to prepare a compound of the formula: ##STR17## inwhich R'₁, R'₂, Z, p and q are as defined above, and to perform anucleophilic substitution with a hydrogen sulfide salt or an amine ofthe formula H₂ NR₁₃, in a solvent such as an alcohol, an ether, DMF or amixture thereof, at a temperature between 5° C. and the refluxtemperature.

The 1,3-dihydroindol-2-ones of formula (II') are obtained from thecorresponding diols protected for example by a tetrahydropyran-2-ylgroup. The reaction can be carried out with dibromotriphenylphosphoraneaccording to J. Chem. Soc., Chem. Commun., 1989, 1619.

The compounds (II) in which R₃ and R₄, together with the carbon to whichthey are bonded, form a pyrrolidine, N-alkylpyrrolidine, piperidine orN-alkylpiperidine ring are described by M. J. Kornet in J. Med. Chem.,1976, 19 (7), 892-899.

In particular, horsfiline of the formula: ##STR18## is an alkaloiddescribed in A. Jossang et al., J. Chem., 1991, 56 (23), 6527-6530.

To prepare a compound of formula (II) in which R₃ and R₄, together withthe carbon to which they are bonded, form a tricyclo 5.2.1.0²,6 !decaneor a tricyclo 5.2.1.0²,6 !dec-8-ene, a compound (VII') or, respectively,a compound (VII") of the formulae ##STR19## in which Z is as definedabove, is reacted with a compound of formula (VII). Compounds (VII') and(VII") substituted by one or more C₁ -C₇ -alkyl groups are used toprepare compounds (II) in which said carbocycles are substituted.

A compound of formula (II) in which R₃ and R₄, together with the carbonto which they are bonded, form a tricyclo 5.2.1.0²,6 !decane can also beprepared by the catalytic hydrogenation of a compound of formula (II) inwhich R₃ and R₄, together with the carbon to which they are bonded, forma tricyclo 5.2.1.0²,6 !dec-8-ene, for example in the presence ofpalladium-on-charcoal or Raney® nickel.

A compound of formula (I) in which R₃ and R₄, together with the carbonto which they are bonded, form a tricyclo 5.2.1.0²,6 !decane can also beprepared by the catalytic hydrogenation of a compound of formula (I) inwhich R₃ and R₄, together with the carbon to which they are bonded, forma tricyclo 5.2.1.0²,6 !dec-8-ene, for example in the presence ofpalladium-on-charcoal or Raney® nickel.

To prepare a compound (II) in which R₃ and R₄, together with the carbonto which they are bonded, form an indane or a hexahydroindane, acompound (VIII') or, respectively, a compound (VIII") of the formulae:##STR20## in which Z is defined as indicated above for (VIII), isreacted with a compound (VII). Compounds (VIII') and (VIII") substitutedby one or more C₁ -C₇ -alkyl groups are used to prepare compounds (II)in which the indane or hexahydroindane is substituted.

In the same way, the method of A. S. Kende and J. C. Hodges describedabove is used to prepare compounds of formula (II) in which thesubstituents R₃ and R₄, together with the carbon to which they arebonded, form a saturated or unsaturated C₃ -C₁₂ hydrocarbon ringsubstituted by one or more (C₁ -C₇)alkyl groups or by a group selectedfrom an oxo group, a C₃ -C₅ -spirocycloalkyl, a hydroxyl substituted bya (C₁ -C₇)alkyl, a (C₁ -C₂)alkoxy(C₁ -C₄)alkyl, a phenyl(C₁-C₂)alkoxy(C₁ -C₄)alkyl, a tetrahydrofuranyl and a tetrahydropyranyl. Toobtain the compounds of formula (I) in which R₃ and R₄, together withthe carbon to which they are bonded, form a saturated or unsaturated C₃-C₁₂ hydrocarbon ring substituted by a hydroxyl, the correspondingcompounds of formula (I) in which the hydroxyl group is substituted by a(C₁ -C₂)alkoxy(C₁ -C₄)alkyl, a tetrahydrofuranyl or a tetrahydropyranylare deprotected. This deprotection is effected in an acid medium, forexample in the presence of a mineral or organic acid, in an alcohol orether solvent such as THF, at a temperature between 15° C. and thereflux temperature; the deprotection can be carried out for example inthe presence of hydrochloric acid or pyridinium toluenesulfonate in analcohol.

The compounds of formula (II) in which R₃ and R₄, together with thecarbon to which they are bonded, form either an optionally fused,saturated or unsaturated C₃ -C₁₂ hydrocarbon ring substituted by an oxogroup, or a group --(CH₂)_(p) --X--(CH₂)_(q) -- in which X is a groupSO, SO₂ or N(O)R₁₃, are prepared by known oxidation reactions startingfrom the corresponding compounds of formula (II) in which R₃ and R₄,together with the carbon atom to which they are bonded, respectivelyform either an optionally fused, saturated or unsaturated C₃ -C₁₂hydrocarbon ring substituted by a hydroxyl, or a group --(CH₂)_(p)--X--(CH₂)_(q) -- in which X is a sulfur atom or a group NR₁₃.

For example, the oxidation of secondary alcohols to ketones can becarried out in the presence of chromium oxide complexes such aspyridinium chlorochromate, in an inert solvent such as methylenechloride, or with oxidizing agents such as DMSO, by the methodsdescribed in Tetrahedron, 1978, 34, 1651-1660.

The oxidation of the compounds (II) containing a sulfur or nitrogen atom(X=S, NR₁₃) can be effected in the presence of hydrogen peroxide orperacids such as peracetic or metachloroperbenzoic acid, in inertsolvents such as ketones or acetic acid, at temperatures between 0° C.and 50° C.

The derivatives (VII) are known or are prepared by known methods. Anexample which may be cited is J. V. RajanBabu in J. Org. Chem., 1986,51, 1704-1712.

The compounds of formula (II) which carry certain substituents R'₁ andR'₂ on their benzene moiety are used as precursors for the preparationof compounds of formula (II) which carry other substituents R'₁ and R'₂.For example, the compounds (II) in which R'₁ and/or R'₂ =H can benitrated with the conventional reagents; they can also be acylated byreaction with an acid chloride of the formula RCOCl, in which R is a C₁-C₇ -alkyl, in the presence of a Lewis acid such as aluminum chloride,in order to prepare a compound (II) in which R'₁ and/or R'₂ =--COR. Thecompound (II) in which R'₁ is an amino group is prepared by thecatalytic hydrogenation of a compound (II) in which R'₁ is a nitro groupand R'₂ is hydrogen.

The halides of formula (III) are known or are prepared by known methods.

Publications describing the following halogenomethylbenzene derivativesmay be cited by way of example:

1,2,4-, 4,2,1- or 2,4,1-chloromethylmethyl methoxybenzene: Bull. Soc.Chim. France, 1937, 4, 1092.

2-Chloromethyl-1,3-dimethoxybenzene: Chem. Listy, 1953, 47, 601-612.

1-Bromomethyl-2-methoxy-4-nitrobenzene: Sci. Sinica (Peking), 1962, 11,483-498.

1-Bromomethyl-2-methyl-4-nitrobenzene: Pharmazie, 1969, 24 (1), 29-32.

1-Bromomethyl-2-methoxy-4-nitrobenzene: Bull.Soc. Chim. France, 1962,2255.

1-Bromomethyl-4-methoxy-2-nitrobenzene: Zh. Obshch. Khim., 1963, 33 (8),2792-2793.

Methyl 4-bromomethyl-3-methoxybenzoate: European patent application EP179 619.

Ethyl 2-bromomethyl-6-methoxybenzoate: J. Org. Chem., 1983, 48,3439-3444.

Ethyl 2-Bromomethyl-4,5-dimethoxybenzoate and ethyl2-bromomethyl-3,4-dimethoxybenzoate: J. Org. Chem., 1968, 33, 494.

Methyl 4-bromomethyl-2-methoxybenzoate: Bull. Soc. Chim. France, 1962,2255.

1-Bromomethyl-4-cyano-2-methoxybenzene: J. Med. Chem., 1990, 33,2437-2451.

In general, the halogenomethylbenzene derivatives can be prepared byreacting N-bromosuccinimide with the corresponding methylbenzenederivatives. The reaction is carried out in a solvent such as carbontetrachloride, in the presence of dibenzoyl peroxide. Ahalogenomethylbenzene derivative can also be prepared from acorresponding hydroxymethylbenzene derivative by reaction withphosphorus tribromide in ether.

In another process, the halogenomethylbenzene derivatives of formula(III) can be prepared from the corresponding alcohol by reaction withthionyl chloride in order to prepare a methylbenzene chloride.

For certain meanings of the substituents R₁, R₂, R₅ and/or R₆, thecompounds (I) according to the invention can be prepared from aprecursor of formula (I') substituted by a group R'₁, R'₂, R'₅ and/orR'₆, called a precursor group of R₁, R₂, R₅ and/or R₆, using methodsknown to those skilled in the art.

The following description relates to the preparation of the compounds offormula (I) carrying substituents R₁ and/or R₆ ; the same methods areapplied to the preparation of the compounds in which the substituents R₂and/or R₅ have the meanings indicated for R₁ and/or R₆.

The compounds (I) in which R₁ and/or R₆ is a hydroxyl can be obtained bythe catalytic hydrogenation of a compound of formula (I') in which R'₁and/or R'₆ if a benzyloxy, for example in the presence ofpalladium-on-charcoal. These compounds can also be prepared fromanalogous compounds of formula (I') in which R'₁ and/or R'₆ is an aminogroup by using the method described in J. Org. Chem., 1977, 42, 2053.

The compounds of formula (I) in which R₁ and/or R₆ is a (C₁ -C₇)alkoxycan be prepared directly by the process according to the inventionstarting from the correctly substituted compounds of formulae (II) and(III).

The compounds (I') in which R'₁ and/or R'₆ is a hydroxyl can also beused to prepare compounds (I) in which R₁ and/or R₆ is a (C₁ -C₇)alkoxyby reaction with a C₁ -C₇ -alkyl halide in the presence of a base suchas a metal hydride or an alkali metal or alkaline earth metal carbonatelike K₂ CO₃ or Cs₂ CO₃, in a solvent such as THF or DMF. Likewise, thecompounds of formula (I) in which R₁ and/or R₆ is an ω-aminoalkoxy areprepared by reacting an ω-chloroalkylamine with the compounds in whichR'₁ and/or R'₆ =OH; again, the compounds in which R₁ and/or R₆ is anω-hydroxyalkoxy are prepared by reaction with a chloroalkyl alcohol ; inthe particular case of the preparation of a compound (I) in which R₁and/or R₆ =--O(CH₂)₂ OH, it is also possible to react ethylene carbonatewith a compound (I') in which R'₁ and/or R'₆ =--OH.

The halogenoalkoxybenzyl halides (III, R'₆ =ω-halogenoalkoxy) are usedfor the preparation of compounds according to the invention in which thesubstituent R₆ is an ω-aminoalkoxy which is unsubstituted or substitutedby one or two alkyls, according to the following equation:

    --O--Alk'--Hal+NHAA'→--O--Alk'--NAA'

in which Alk' is a (C₂ -C₇)alkyl and A and A' independently of oneanother are H or a (C₁ -C₇)alkyl.

The compounds of formula (I) in which R₁ and/or R₆ is a formyloxy, a (C₁-C₇)alkylcarbonyloxy or a benzoyloxy are obtained by reacting forexample, the formic acid in the presence of dicyclohexylcarbodiimide (J.HUANG et al. J. Chem. Research (S), 1991, 292-293) or respectively byreacting an acid halide or an anhydride with a compound (I') in whichR'₁ and/or R'₆ is a hydroxyl.

The compounds of formula (I) in which R₆ is a group --OR₇, R₇ being anω-carbamoyl(C₁ -C₇)alkyl which is free or substituted by one or two C₁-C₇ -alkyls, can be prepared from a compound (I') in which R'₆ is agroup --OR₇, R₇ being an ω-carboxy(C₁ -C₇)alkyl esterified by a C₁ -C₇-alkyl. This preparation is carried out in a manner conventional tothose skilled in the art by reaction with a correctly chosen amine.

The compounds of formula (I) in which R₆ is a (C₁ -C₇)alkoxycarbonyl canbe prepared directly by the process according to the invention. Usingmethods known to those skilled in the art, they make it possible toobtain the compounds of formula (I) in which R₆ is a carboxyl group.

The compounds of formula (I') in which R'₆ is a benzyloxycarbonyl makeit possible, by catalytic hydrogenation, to obtain the compounds (I) inwhich R₆ is a carboxyl. Reaction with a thionyl halide gives thecompounds of formula (I') in which R'₆ is a halogenocarbonyl. Suchcompounds are reacted with a compound HNR₁₇ R₁₈ in order to preparecompounds of formula (I) in which R₆ is a carbamoyl substituted by R₁₇and R₁₈. The compounds of formula (I') in which the substituent R'₆ is aphenoxycarbonyl can also be used to obtain the compounds of formula (I)in which R₆ is a phenylcarbamoyl or a (C₁ -C₇)alkylcarbamoyl by reactionwith an aniline or a (C₁ -C₇)alkylamine. An aniline substituted on thephenyl by anyone of the phenyl substituents as defined for Ar, or analkylamine substituted on the alkyl by R₂₆ makes it possible to obtaincompounds of formula (I) in which R₆ is a phenylcarbamoyl substituted onthe phenyl or, respectively, an alkylcarbamoyl substituted on the alkylby R₂₆.

The compounds of formula (I') in which R'₆ is a carboxyl can be used toobtain the compounds of formula (I) in which R₆ is a group --CONR₁₇ R₁₈by reaction with a compound of the formula HNR₁₇ R₁₈, in the presence ofBOP and an amine such as diisopropylethylamine.

In the same way, the compounds of formula (I) which R₆ is a group--CONHCR₁₀ R₂₃ COR₁₂ are prepared from compounds of formula (I') inwhich R'₆ is either a group --COCl or a phenoxycarbonyl group byreaction with H₂ NCR₁₀ R₂₃ COR₁₂. They can also be prepared fromcompounds of formula (I') in which R'₆ is a carboxyl by reaction with acompound H₂ NCR₁₀ R₂₃ COR₁₂, in the presence of BOP and an amine such asdiisopropylethylamine.

The compounds of formula (I) in which R₆ is group --COR₂₅ are preparedfrom corresponding compounds (I') in which R'₆ is a phenoxycarbonyl byreaction with R₂₅ H.

A compound (I) in which R₆ is a thiocarbamoyl be prepared by reactingLawesson's reagent with compound (I) in which R₆ is the correspondingcarbamoyl.

A compound of formula (I') in which R'₆ is nitro group makes it possibleto obtain a compound (I) which R₆ is an amino group by catalytichydrogenation, for example in the presence of platinum oxide, Raney®nickel or palladium-on-charcoal, or by chemical reduction, for examplein the presence of tin or iron in an acid medium; other compounds inwhich the amino group is substituted can then be prepared usingreactions well known to those skilled in the art.

To prepare compounds of formula (I) in which R₁ and/or R₆ is a (C₁-C₇)monoalkylamino, a compound of formula (I') in which R'₁ and/or R'₆is an amino group is reacted with an aldehyde or a ketone in an acidmedium, in the presence of a reducing agent such as sodiumcyanoborohydride; the compounds (I) in which R₁ and/or R₆ is adialkylamino are prepared by an identical reaction.

The compounds of formula (I) in which R₆ is an amino group substitutedby a benzyl, which is itself optionally substituted, or by a C₃ -C₈-alkene can be prepared by reacting a benzyl chloride or a C₃ -C₈-chloroalkene with a compound of formula (I') in which R'₆ is an aminoor (C₁ -C₇)alkylamino group.

The compounds of formula (I) in which R₆ is a Δ3-pyrrolin-1-yl group areprepared by reacting cis-1,4-dichlorobut-2-ene with the compounds offormula (I') in which R'₆ is an amino group, in the presence of a basesuch as triethylamine and under an inert atmosphere. The compounds offormula (I) in which R₆ is a pyrrolidin-1-yl group are then prepared byhydrogenation. The reaction of cis-1,4-dichlorobut-2-ene with thecompounds (I') in which R'₆ is an amino group can also be carried out inair, in the presence of a base such as sodium carbonate, under whichconditions it results in the formation of a mixture of a compound offormula (I) in which R₆ is a Δ3-pyrrolin-1-yl group and a compound offormula (I) in which R₆ is a pyrrol-1-yl group, which can be separatedby chromatography.

The compounds of formula (I) in which R₆ is an isoindolin-2-yl group areprepared by reacting α,α'-dibromo-o-xylene with the compounds of formula(I') in which R'₆ is an amino group, in the presence of a base such astriethylamine, and in a solvent such as dimethylformamide, under reflux.

The compounds of formula (I) in which R₆ is a1-methyl-2,4-dioxoimidazolin-3-yl group (NR₈ R₉ =N-methylhydantoin) areprepared in two steps: Sarcosine is reacted with a compound of formula(I') in which R'₆ is a phenoxycarboxamido, in the presence of a basesuch as triethylamine, to give a compound of formula (I') in which R'₆is an N'-carboxymethyl-N'-methylureido; the previously obtained productthen cyclizes on heating at 100° C. under vacuum.

In a similar manner, a compound of formula (I) in which R₆ represents a2,4-dioxoimidazolin-3-yl (NR₈ R₉ hydantoin) may be prepared by reactingglycine with a compound of formula (I') as hereinabove defined.

If R'₁ and/or R'₆ is an amino, it is also possible to perform anitrosation, for example in the presence of nitrous acid or sodiumnitrite, in order to prepare a compound (I') in which R'₁ and/or R'₆ isa diazonium salt; the compounds (I) according to the invention in whichR₁ and/or R₆ is a cyano, a halogeno or a C₁ -C₇ -alkylthio are thenobtained by reactions known to those skilled in the art. Finally,compounds (I) in which R₁ and/or R₆ is a group of the formula RCONH--,ROCONH--, RNHCONH-- or RSO₂ NH--, in which R is a (C₁ -C₇)alkyl, a groupAr or a group --CH₂ Ar, can be prepared by conventional reactionsstarting from compounds (I') in which R'₁ and/or R'₆ =NH₂.

The compounds of formula (I) in which R₆ is a group --CH₂ NH₂ areprepared from analogous compounds of formula (I') in which R'₆ is acyano group by the method described in J. Med. Chem., 1990, 33,2437-2451. These compounds are used to prepare the compounds of formula(I) in which R₆ is a group --CH₂ NR₈ R₉, R₉ and/or R₈ being other thanhydrogen, by methods known to those skilled in the art.

The compounds (I) in which R₆ is a group --NR₈ R₉, R₉ being a formyl, a(C₁ -C₇)alkylcarbonyl, a (C₃ -C₇)cycloalkylcarbonyl, an optionallysubstituted benzoyl, a pyridylcarbonyl, a methylpyridylcarbonyl or athienylcarbonyl, are obtained by reacting the formic acid in thepresence of acetic anhydride with a compound (I') in which R'₆ is anamino group or respectively by reacting the appropriate anhydride or theappropriate acid chloride with a compound (I') in which R'₆ is an aminogroup, in the presence of an amine such as triethylamine.

In the same way, the acid chloride R₁₁ R₁₉ NCR₁₀ R₂₃ COCl is reactedwith a compound of formula (I') in which R'₆ is an amino group in orderto prepare a compound of formula (I) in which R₆ is an amino substitutedby --COCR₁₀ R₂₃ NR₁₁ R₁₉.

To prepare a compound of formula (I) in which R₆ is a group --NR₈CO--(C₂ -C₇)alkyl-NR₁₁ R₁₉, a halogeno(C₃ -C₈)acyl halide, such as, forexample, 3-chloropropionyl chloride or 4-chlorobutyryl chloride, isreacted with a compound of formula (I') in which R'₆ is a group --NHR₈,in the presence of a base such as triethylamine; the compound obtainedis then reacted with an amine HNR₁₁ R₁₉ to give the compound of formula(I) designated above.

Likewise, a compound of formula (I) in which R₆ is a group --NR₈ CO--(C₁-C₇)alkyl-O--CH₂ --C₆ H₅ is prepared by reacting an ω-benzyloxy-(C₁-C₇)alkylcarbonyl halide with a compound of formula (I') in which R'₆ isa group --NHR₈. Hydrogenation of the previous compound, in the presenceof a catalyst such as 5% palladium-on-charcoal, gives a compound offormula (I) in which R₆ is a group --NR₈ CO--(C₁ -C₇)alkyl-OH.

According to another preparatory example, a compound (I) in which R₆ isa (C₁ -C₇)alkylsulfonamido group, a benzylsulfonamido, a group --NHSO₂Ar or a group --NHSO₂ NR₁₆ R₂₂ is obtained by reacting a (C₁-C₇)alkylsulfonyl halide, a benzylsulfonyl halide, a compound ArSO₂ Clor a compound R₂₂ R₁₆ NSO₂ Cl, respectively, with a compound (I') inwhich R'₆ is an amino group.

The compounds (I') in which R'₆ is an amino group are also useful forthe preparation of compounds in which this amino group is substituted bya group --(CH₂)_(t) -COR₁₂. In this case, a compound of the formulaHal-(CH₂)_(t) -COOAlk, in which Hal is a halogen, for example bromine,and Alk is a C₁ -C₇ -alkyl, is reacted with (I') in the presence ofcuprous chloride; if required, the resulting ester is converted to theacid or an amide. A compound (I) in which R₆ is a group --NHCO(CH₂)₂ CO₂H or --NHCO(CH₂)₃ CO₂ H can be prepared by reacting an anhydride, suchas succinic anhydride or glutaric anhydride, with a compound (I') inwhich R'₆ is an amino. If required, the resulting acid is converted toan ester or an amide.

It is also possible to react ethyloxalyl chloride or respectively aethylmalonyl chloride with a compound (I') in which R'₆ is an amino inorder to prepare a compound (I) in which R₆ is a group --NHCOCO₂ Et orrespectively a group --NHCOCH₂ CO₂ Et.

In the same way, the compounds of formula (I) in which R₆ is an aminogroup substituted by a group --CR₁₀ R₂₃ COR₁₂ are prepared by reacting acompound of the formula Hal-CR₁₀ R₂₃ COR₁₂ with the correspondingcompounds (I') in which the substituent R'₆ is an amino.

A compound (I) in which R₆ is an amino group substituted by analkoxycarbonyl, a phenoxycarbonyl or a benzyloxycarbonyl is prepared byreacting a C₁ -C₇ -alkyl, phenyl or benzyl chloroformate with a compound(I') in which the substituent R'₆ is an amino.

Likewise, a compound of formula (I) in which R₆ is aphenoxythiocarbonylamino is obtained by reacting a phenoxythiocarbonylchloride with a compound of formula (I') in which R'₆ is an amino group.

A compound of formula (I) in which R₆ is a ureido or a thioureido isprepared by reacting ammonia with a compound of formula (I') in whichR'₆ is an amino group substituted by a phenoxycarbonyl or aphenoxythiocarbonyl; such a compound of formula (I') is reacted with acorrectly substituted aniline or a correctly substituted C₁ -C₇-monoalkylamine or C₁ -C₇ -dialkylamine in order to prepare a compoundof formula (I) in which R₆ is a correctly substituted N'-phenylureido ora correctly substituted N'-alkylureido or N',N'-dialkylureido in whichthe alkyl is C₁ -C₇.

It is also possible to prepare other compounds (I) in which R₆ is aureido (--NHCONR₁₄ R₂₄) or a thioureido (--NHCSNR₁₄ R₂₄) by reacting acompound NHR₁₄ R₂₄ with a compound (I') in which R'₆ is aphenoxycarbonylamino or, respectively, phenoxythiocarbonylamino group.

A further possibility is to prepare a compound (I) in which R₆ is aureido (--NHCONR₁₄ R₂₄) or a thioureido by reacting a carbamoyl chloride(ClCONR₁₄ R₂₄) or, respectively, a thiocarbamoyl chloride with acompound of formula (I') in which R'₆ is an amino group.

It is also possible to prepare a compound (I) in which R₆ is athioureido by reacting Lawesson's reagent with a compound (I') in whichR'₆ is the corresponding ureido.

The compounds (I) in which R₆ is a guanidino group which isunsubstituted or monosubstituted or disubstituted by a C₁ -C₇ -alkyl, aphenyl or a benzyl can be prepared from the compounds (I') in which R'₆is a phenoxyamido group by reaction with cyanamide or a derivativethereof correctly substituted on the nitrogen.

The compounds (I) in which R₆ is a guanidino group substituted in the2-position by a cyano are prepared in two steps: DimethylN-cyanodithioiminocarbonate is reacted with a compound (I') in which R'₆is an amino, in a solvent such as n-butanol, under reflux, to give acompound (I') in which R'₆ is a group --NHC(SCH₃)═N--CN; reaction of theprevious compound with an appropriate amine gives the expected compound(I).

It is also possible to prepare a compound (I) in which R₆ is an aminogroup substituted by a (C₁ -C₇)alkylcarbamoyl or a phenylcarbamoyl byreacting an alkyl or phenyl isocyanate with a compound (I') in which thesubstituent R'₆ is an amino.

Furthermore, a compound (I) in which R₆ is a sulfamoyl group substitutedby R₂₀ and R₂₁ is prepared by reacting a compound --HNR₂₀ R₂₁ with acompound of formula (I') in which R'₆ is a halogenosulfonyl group.

The affinity of the compounds according to the invention for thevasopressin receptors was determined in vitro using the method describedin C. J. Lynch et al., J. Biol. Chem., 1985, 260 (5), 2844-2851. Thismethod consists in studying the displacement of tritiated vasopressinbound to the V₁ sites of rat liver membranes. The concentrations of thecompounds according to the invention which cause a 50% inhibition of thebinding of tritiated vasopressin (IC₅₀) are low, ranging down to 10⁻⁷ M.

The affinity of the compounds (I) according to the invention for the V₂receptors was measured on a bovine kidney membrane preparation by amethod adapted from P. Crause et al., Molecular and CellularEndocrinology, 1982, 28, 529-541, and F. L. Stassen et al., J.Pharmacol. Exp. Ther., 1982, 223, 50-54. The compounds according to theinvention inhibit the binding of tritiated arginine vasopressin to thereceptors of the membrane preparation. The IC₅₀ values of the compoundsaccording to the invention are low, ranging down to 10⁻⁸ M.

The antagonistic activity of the compounds according to the inventiontowards the V₂ receptors was demonstrated by the adenylate cyclaseactivity assay performed by a method adapted from M. Laburthe et al.,Molecular Pharmacol., 1986, 29, 23-27. A bovine kidney membranepreparation is used and each product is incubated for 10 minutes at 37°C., either by itself or in the presence of AVP (arginine vasopressin) ata concentration of 3.10⁻⁸ M. The cyclic AMP (cyclic adenosinemonophosphate) produced is measured by radioimmunoassay. Theconcentration which causes a 50% inhibition (IC₅₀) of the stimulation ofadenylate cyclase induced by 3.10⁻⁸ M AVP is determined. The IC₅₀ valuesdeter mined are of the order of 10⁻⁷ M, ranging down to 10⁻⁸ M.

The agonistic or antagonistic activity of the compounds according to theinvention, administered orally, towards the vasopressin receptors isevaluated in hyperhydrated rats (OFA, Sprague-Dawley strain) treatedwith vasopressin. The antagonistic activity of the compounds accordingto the invention was also evaluated in normally hydrated rats (OFAstrain or Sprague-Dawley strain) by the technique described in Br. J.Pharmacol., 1992, 105, 787-791. The diuretic effect was observed forsome of the compounds at a dose of 10 mg/kg.

Likewise, the affinity of the compounds (I) according to the inventionfor the oxytocin receptors was determined in vitro by the displacementof a radioiodinated oxytocin analog bound to the receptors of agestating rat mammary gland membrane preparation by a technique similarto that described by J. Eland et al. in Eur. J. Pharmacol., 1987, 147,197-207. The IC₅₀ values of the compounds according to the inventionreach 10⁻⁷ M.

The compounds according to the invention are active after administrationby different routes, especially orally.

No signs of toxicity are observed with these compounds at thepharmacologically active doses.

Thus the compounds according to the invention can be used in thetreatment or prevention of various vasopressin-dependent oroxytocin-dependent complaints, cardiovascular complaints such ashypertension, pulmonary hypertension, cardiac insufficiency, myocardialinfarction or coronary vasospasm, in particular in smokers, unstableangina and PTCA (percutaneous transluminal coronary angioplasty),cardiac ischemia, hemostatic disorders, especially hemophilia, and vonWillebrand's syndrome, complaints of the central nervous system, forexample migraine, cerebral vasospasm, cerebral hemorrhage, cerebraledemas, depression, anxiety, psychotic states and memory disorders,complaints of the renal system, such as edemas, renal vasospasm,necrosis of the renal cortex, hyponatremia, hypokalemia and SchwartzBartter's syndrome, complaints of the gastric system, such as gastricvasospasm, hepatocirrhosis, ulcers, the pathology of vomiting, forexample nausea, including nausea due to chemotherapy, travel sickness orelse the syndrome of inappropriate secretion of antidiuretic hormone(SIADH), diabetes insipidus and enuresis. The compounds according to theinvention can also be used in the treatment of disorders of sexualbehavior; in women, the compounds according to the invention can be usedfor treating dysmenorrhea or premature labor. The compounds according tothe invention can also be used in the treatment of small cell lungcancer, hyponatremic encephalopathy, Raynaud's disease, pulmonarysyndrome and glaucoma and in postoperative treatments, especially afterabdominal surgery.

The present invention further relates to pharmaceutical compositionscontaining an effective dose of a compound according to the invention,or a pharmaceutically acceptable salt, and suitable excipients.

Said excipients are chosen according to the pharmaceutical form and thedesired mode of administration.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical,intratracheal, intranasal, transdermal or rectal administration, theactive principles of formula (I) above, or their salt where appropriate,can be administered to animals and humans in unit forms ofadministration, mixed with conventional pharmaceutical carriers, for theprophylaxis or treatment of the above disorders or diseases. Theappropriate unit forms of administration include forms for oraladministration, such as tablets, gelatin capsules, powders, granules andsolutions or suspensions to be taken orally, forms for sublingual,buccal, intratracheal or intranasal administration, forms forsubcutaneous, intramuscular or intravenous administration and forms forrectal administration. For topical application, the compounds accordingto the invention can be used in creams, ointments or lotions.

To obtain the desired prophylactic or therapeutic effect, the dose ofactive principle can vary between 0.01 and 50 mg per kg of body weightand per day.

Each unit dose can contain from 0.5 to 1000 mg, preferably from 1 to 500mg, of active ingredients in combination with a pharmaceutical carrier.This unit dose can be administered 1 to 5 times a day so as toadminister a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg.

If a solid composition is prepared in the form of tablets, the mainactive ingredient is mixed with a pharmaceutical vehicle such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets can be coated with sucrose, a cellulose derivative orother appropriate substances, or else they can be treated so as to havea sustained or delayed activity and so as to release a predeterminedamount of active principle continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with a diluent and pouring the resulting mixture intosoft or hard gelatin capsules.

A preparation in the form of a syrup or elixir or for administration inthe form of drops can contain the active ingredient together with asweetener, which is preferably calorie-free, methylparaben andpropylparaben as antiseptics, a flavoring and an appropriate color.

The water-dispersible powders or granules can contain the activeingredient mixed with dispersants or wetting agents, or suspensionagents such as polyvinylpyrrolidone, as well as with sweeteners or tastecorrectors.

Rectal administration is effected using suppositories, which areprepared with binders melting at the rectal temperature, for examplecocoa butter or polyethylene glycols.

Parenteral administration is effected using aqueous suspensions,isotonic saline solutions or sterile and injectable solutions whichcontain pharmacologically compatible dispersants and/or wetting agents,for example propylene glycol or butylene glycol.

The active principle can also be formulated as microcapsules, ifappropriate with one or more carriers or additives.

In addition to the products of formula (I) above or one of thepharmaceutically acceptable salts, the compositions of the presentinvention can contain other active principles which may be useful in thetreatment of the disorders or diseases indicated above.

Thus the present invention further relates to pharmaceuticalcompositions in which several active principles are present inassociation, one of them being a compound according to the invention.

Thus, according to the present invention, it is possible to preparepharmaceutical compositions in which a compound according to theinvention is present in association with a compound which acts on therenin-angiotensin system, such as a converting enzyme inhibitor, anangiotensin II antagonist or a renin inhibitor. A compound according tothe invention can also be associated for example with a peripheralvasodilator, a calcium inhibitor, a beta-blocker, an alpha-1-blocker ora diuretic. Such compositions will be useful in particular in thetreatment of hypertension or heart failure.

It is also possible to associate two compounds according to theinvention, namely a specific V₁ receptor antagonist with a specific V₂receptor antagonist, or else a specific V₁ receptor antagonist with aspecific oxytocin antagonist.

These associations will make it possible to reinforce the therapeuticactivities of the compounds according to the invention.

Preparation of the 1,3-dihydroindol-2-ones

Preparation 1:

1,3-Dihydro-4,6-dimethyl-3-spirocyclohexaneindol-2-one

This compound is prepared according to Moore and Plant in J. Chem. Soc.,1951, 3475.

A mixture containing 15 ml of quinoline and 10 g of calcium oxide isrefluxed under an inert atmosphere and 5 g of the3,5-dimethylphenylhydrazide of cyclohexanecarboxylic acid (IV, R'₁, R'₂=CH₃, CR₃ R₄ =cyclohexane) are added over 30 minutes. The reactionmedium is cooled and then poured into an ice/hydrochloric acid mixture.Extraction is carried out with ethyl acetate and the extract is washedwith 1N hydrochloric acid and with water until the washings are neutral,and then dried over Na₂ SO₄ and concentrated under vacuum to give abrown solid. Trituration in iso ether gives the expected compound.M.p.=223° C.

The 1,3-dihydroindol-2-one derivatives described in Table 1 below areobtained by following the same procedure and varying the startinghydrazide.

These compounds are purified by chromatography on a silica column usingDCM as the eluent or by chromatography on an alumina column using DCM oriso ether as the eluent.

                  TABLE 1                                                         ______________________________________                                         ##STR21##                                                                    R'.sub.1  R'.sub.2   CR.sub.3 R.sub.4                                                                        M.p. °C.                                ______________________________________                                        5-Cl      H          cyclobutane                                                                             191                                            5-Cl      H          cyclopentane                                                                            189                                            5-Cl      H          cyclohexane                                                                             186                                            H         H          cyclohexane                                                                             123-124                                        5-CH.sub.3                                                                              H          cyclohexane                                                                             164                                            5-CH.sub.3 O                                                                            H          cyclohexane                                                                             226                                            6-Cl      H          cyclohexane                                                                             168                                            5-CF.sub.3 O                                                                            H          cyclohexane                                                                             164                                            5-C.sub.6 H.sub.5 O                                                                     H          cyclohexane                                                                             160                                            ______________________________________                                    

Preparation 2:

The 1,3-dihydro-3-spirocyclohexaneindol-2-one described in Table 1 abovecan also be obtained by alkylation of the indol-2-one using the processaccording to A. S. Kende and J. C. Hodges or a variant described below.

A solution of 30 g of 1,3-dihydroindol-2-one in 900 ml of THF is kept at-40° C. under a nitrogen atmosphere and 101 g of potassium tert-butylateare added. The temperature is allowed to rise to 0° C. over 1 hour, themixture is then cooled to -60° C. and a solution of 52 g of1,5-dibromopentane in 50 ml of THF is added dropwise. After 30 minutesat -60° C., the temperature is allowed to rise to RT, 30 ml of water arethen added and the solvent is evaporated off under reduced pressure. Theresidue is taken up with 500 ml of DCM and 200 ml of water, theinsoluble material is then filtered off and the organic phase isseparated off, washed with 100 ml of water, dried over magnesium sulfateand evaporated under vacuum. The residue is chromatographed on silicausing a cyclohexane/ether mixture as the eluent to give the expectedcompound, which is recrystallized from heptane. m=34 g. M.p.=123°-124°C.

A similar procedure can be applied starting from other1,3-dihydroindol-2-ones and other alkylating agents.

By way of example, among the starting compounds of formula (VII),5-chloro-1,3-dihydroindol-2-one is described by Wright in J. Am. Chem.Soc., 1956, 78, 221, and by RajanBabu in J. Org. Chem., 1986, 51, 1704.4-Chloro-1,3-dihydroindol-2-one can be prepared from2-chloro-6-nitrotoluene by the method described in J. Am. Chem. Soc.,1956, 78, 221.

1,3-Dihydro-5-methoxyindol-2-one is prepared from 4-methoxyaniline bythe method described in J. Am. Chem. Soc., 1974, 96, 5512. In the sameway, various 1,3-dihydroindol-2-ones are prepared from the appropriateaniline derivative.

Preparation 3:

5-Ethoxy-1,3-dihydroindol-2-one

A--3-Methylthio-5-ethoxy-l,3-dihydroindol-2-one

23.6 g of ethyl methylthioacetate in 60 ml of DCM are added to asolution, cooled to about -70° C., of 12.5 g of chlorine in 400 ml ofDCM. After stirring for 5 minutes at the same temperature, a solution of4-ethoxyaniline (48.3 g) in 120 ml of DCM is added. The mixture isstirred for one hour at about -70° C., 39.3 ml of triethylamine areadded and the resulting mixture is allowed to warm up to roomtemperature. 200 ml of water are added and the organic phase isdecanted, dried over magnesium sulfate and evaporated under reducedpressure. The residue is taken up with 500 ml of isopropanol and 20 mlof concentrated hydrochloric acid. The mixture is stirred for about 16hours at room temperature and filtered and the precipitate is separatedoff. The filtrate is concentrated under reduced pressure to give theexpected product.

B--5-Ethoxy-1,3-dihydroindol-2-one

The above solid, in 1500 ml of isopropanol, is dethiomethylated in thepresence of 100 g of Raney® nickel (80 to 100 m² per g), under reflux,for 3 hours, under a nitrogen atmosphere. The mixture is filtered ontalc, the material on the filter is rinsed with 1000 ml of isopropanoland the filtrate is concentrated under reduced pressure. 16 g of theexpected product are isolated after recrystallization from toluene.M.p.=156° C.

The following are isolated in the same manner starting from thecorresponding anilines:

    ______________________________________                                        5-benzyloxy-1,3-dihydroindol-2-one                                                                    m.p. = 152° C.                                 5-n-propyl-1,3-dihydroindol-2-one                                                                     m.p. = 136° C.                                 5-ethyl-1,3-dihydroindol-2-one                                                                        m.p. = 152° C.                                 5-(2,2,2-trifluoroethoxy)-1,3-dihydroindol-                                                           m.p. = 145° C.                                 2-one                                                                         5-trifluoromethyl-1,3-dihydroindol-2-one                                                              m.p. = 193° C.                                 5-fluoro-1,3-dihydroindol-2-one                                                                       m.p. = 143° C.                                 ______________________________________                                    

The compounds of formula (II) described below are obtained by followingthe technique described in Preparation 2 and varying the starting1,3-dihydroindol-2-one derivative and the alkylating reagent.

                                      TABLE 2                                     __________________________________________________________________________     ##STR22##                                                                    R'.sub.1                                                                            R'.sub.2                                                                        CR.sub.3 R.sub.4 M.p. °C.                                                                    Alkylating reagent                              __________________________________________________________________________    5-Cl  H cyclohexane      186-189                                                                            Br(CH.sub.2).sub.5 Br                           5-Cl  H cycloheptane     202  Br(CH.sub.2).sub.6 Br                           5-Cl  H 4,4-dimethylcyclohexane                                                                        180  TsO(CH.sub.2).sub.2 C(CH.sub.3).sub.2                                         (CH.sub.2).sub.2 OTs                            5-Cl  H 2-hexahydroindane                                                                              223  1,2-cis-diiodomethyl-                                                         cyclohexane                                     5-CH.sub.3 O                                                                        H 4,4-dimethylcyclohexane                                                                        202  TsO(CH.sub.2).sub.2 C(CH.sub.3).sub.2                                         (CH.sub.2).sub.2 OTs                            5-Cl  H 2-indane         228  α,α'-dibromomethyl-                                               orthoxylene                                     5-Cl  H N-methyl-4-piperidine                                                                          260  Cl(CH.sub.2).sub.2 N(CH.sub.3)                                                (CH.sub.2).sub.2 Cl                             5-Cl  H 4-tetrahydropyran                                                                              223  I(CH.sub.2).sub.2 O(CH.sub.2).sub.2 I           4-Cl  H cyclohexane      215  Br(CH.sub.2).sub.5 Br                           5-BzO H cyclohexane      162  Br(CH.sub.2).sub.5 Br                           5-Cl  H 2,3-dihydro-2-phenalene                                                                        --                                                                                  ##STR23##                                      5-BzO H 4,4-dimethylcyclohexane                                                                        154  TsO(CH.sub.2).sub.2 C(CH.sub.3).sub.2                                         (CH.sub.2).sub.2 OTs                            5-Cl  H 4-spirocyclopentane                                                                            202                                                                                 ##STR24##                                      5-nPr H cyclohexane      151  Br(CH.sub.2).sub.5 Br                           5-EtO H N-tBu-4-piperidine                                                                             --                                                                                  ##STR25##                                      5-Cl  H N-Bz-4-piperidine                                                                              165                                                                                 ##STR26##                                      5-Cl  H N-phenyl-4-piperidine                                                                          188                                                                                 ##STR27##                                      5-Cl  H                                                                                ##STR28##       300                                                                                 ##STR29##                                      5-EtO H 4,4-diethylcyclohexane                                                                         132  TsO(CH.sub.2).sub.2 C(C.sub.2 H.sub.5).sub.2                                  1                                                                             (CH.sub.2).sub.2 OTs                            5-EtO H cyclohexane      163  Br(CH.sub.2).sub.5 Br                           5-EtO H 4,4-dimethylcyclohexane                                                                        178  TsO(CH.sub.2).sub.2 C(CH.sub.3).sub.2                                         (CH.sub.2).sub.2 OTs                            5-EtO H cycloheptane     139  Br(CH.sub.2).sub.6 Br                           5-Et  H 4,4-dimethylcyclohexane                                                                        160  TsO(CH.sub.2).sub.2 C(CH.sub.3).sub.2                                         (CH.sub.2).sub.2 OTs                            5-CF.sub.3 CH.sub.2 O                                                               H 4,4-dimethylcyclohexane                                                                        164  TsO(CH.sub.2).sub.2 C(CH.sub.3).sub.2                                         (CH.sub.2).sub.2 OTs                            H     H 4,4-dimethylcyclohexane                                                                        169  TsO(CH.sub.2).sub.2 C(CH.sub.3).sub.2                                         (CH.sub.2).sub.2 OTs                            5-CF.sub.3                                                                          H 4,4-dimethylcyclohexane                                                                        211  TsO(CH.sub.2).sub.2 C(CH.sub.3).sub.2                                         (CH.sub.2).sub.2 OTs                            5-F   H 4,4-dimethylcyclohexane                                                                        171  TsO(CH.sub.2).sub.2 C(CH.sub.3).sub.2                                         (CH.sub.2).sub.2 OTs                            5-Cl  H                                                                                ##STR30##       120                                                                                 ##STR31##                                      5-EtO H                                                                                ##STR32##       NMR (1)                                                                             ##STR33##                                      5-EtO H                                                                                ##STR34##       208                                                                                 ##STR35##                                      5-EtO H                                                                                ##STR36##       214                                                                                 ##STR37##                                      5-EtO H 4-tetrahydropyrane                                                                             146  I(CH.sub.2).sub.2 O(CH.sub.2).sub.2 I           5-EtO H                                                                                ##STR38##       255                                                                                 ##STR39##                                      __________________________________________________________________________

(1) NMR at 200 MHz in CDCl₃ :

8.3 ppm: s: 1H

7.1 ppm: d: 1H

6.7 ppm: m: 2H

4.7 ppm: s: 2H

3.9 ppm: q: 2H

3.8 ppm: m: 1H

3.4 ppm: s: 3H

2.2 ppm: m: 2H

1.8 ppm: m: 6H

1.4 ppm: t: 3H

Preparation 4:

1,3-Dihydro-3-spiroadamantaneindol-2-one

This compound is prepared according to I. Fleming et al., TetrahedronLetters, 1982, 2053-2056, starting from 2-bromoaniline andadamantan-2-one.

Preparation 5:

1,3-Dihydro-5-nitro-3-spirocyclohexaneindol-2-one

This compound is prepared by the method described in J. Am. Chem. Soc.,1945, 67, 499, by the nitration of1,3-dihydro-3-spirocyclohexaneindol-2-one. M.p.=192° C.

1,3-Dihydro-5-nitro-3-spiroadamantaneindol-2-one is prepared in the samemanner starting from 1,3-dihydro-3-spiroadamantaneindol-2-one. M.p.>260°C.

1,3-Dihydro-5-nitro-3-spiro(4,4-dimethylcyclohexane)indol-2-one is alsoprepared. M.p.=195° C.

Preparation 6:

5-Amino-1,3-dihydro-3-spirocyclohexaneindol-2-one

This compound is prepared by the method described in J. Chem. Soc.,1951, 3475, by the reduction of1,3-dihydro-5-nitro-3-spirocyclohexaneindol-2-one, prepared above.M.p.=176° C.

5-Amino-1,3-dihydro-3-spiroadamantaneindol-2-one is prepared in the samemanner. M.p.=245° C.

Preparation 7:

5-Fluoro-1,3-dihydro-3-spirocyclohexaneindol-2-one

A--5-Diazonium-1.3-dihydro-3-spirocyclohexaneindol-2-onetetrafluoroborate

A solution containing 4 g of5-amino-1,3-dihydro-3-spirocyclohexaneindol-2-one in 9.2 ml of 6Nhydrochloric acid is cooled to 0° C. and 2.27 g of sodium nitrite in 2.6ml of water are added, followed by 2.54 g of sodium tetrafluoroborate in9 ml of water. After stirring for 5 minutes, the precipitate is filteredoff and washed with a 5% solution of tetrafluoroborate, with 3 ml ofmethanol cooled to about 0° C. and then with 5 ml of ether. The saltobtained is dried under vacuum at RT in the presence of phosphoruspentoxide.

B--5-Fluoro-1,3-dihydro-3-spirocyclohexaneindol-2-one

1 g of the compound obtained in step A is placed in 5 ml of xylene andheated at about 115° C. for 2 hours. The mixture is cooled to RT, theprecipitate is filtered off and rinsed with toluene and 0.1 g of activecharcoal is added to the filtrate. After filtration, the solvent isevaporated off under reduced pressure to give 0.45 g of the expectedcompound, which is recrystallized from pentane. M.p.=114° C.

Preparation 8:

5-Cyano-1,3-dihydro-3-spirocyclohexaneindol-2-one

4.78 g of potassium cyanide and 4.95 g of cuprous cyanide are dissolvedat RT in 40 ml of DMSO. The solution is cooled to about 15° C. and 4.15g of the diazonium salt obtained in step A of the previous preparationare added.

After stirring for 30 minutes at RT, 100 ml of water and 100 ml of etherare added and the organic phase is then separated off, dried overmagnesium sulfate and evaporated under reduced pressure. The residue ischromatographed on silica using a cyclohexane/ether mixture as theeluent to give the expected compound, which is recrystallized fromheptane. m=1.4 g. M.p.=216° C.

Preparation 9:

5-Chloro-1,3-dihydro-3-spiroadamantaneindol-2-one

1 g of the p-chlorophenylhydrazide of adamantane-2-carboxylic acid isdissolved in THF and 2.5 ml of a solution of n-butyllithium (1.6M inhexane) are added at -40° C. After stirring for 5 minutes, the mixtureis concentrated under vacuum, the temperature being kept below 30° C. 30ml of 1,2,3,4-tetramethylbenzene are added and the mixture is refluxedfor 1 hour. It is concentrated under reduced pressure, the residue istaken up with normal hydrochloric acid, extraction is carried out withether and the extract is washed, dried and concentrated under vacuum.The oil obtained is chromatographed on a silica column using DCM as theeluent to give 0.3 g of the expected product in the form of a wax, whichis crystallized from iso ether. M.p.=249° C.

Preparation 10:

5-Acetyl-1,3-dihydro-3-spirocyclohexaneindol-2-one

2.56 g of acetyl chloride and then 8.25 g of anhydrous aluminum chlorideare added to a solution, cooled to 5° C., of 4 g of1,3-dihydro-3-spirocyclohexaneindol-2-one in 35 ml of1,2-dichloroethane. The mixture is refluxed for 2 hours, the solvent isevaporated off under reduced pressure and the medium is hydrolyzed with50 g of ice and extracted with ethyl acetate.

The organic phase is washed with water, dried over magnesium sulfate andthen evaporated under reduced pressure. The residue is chromatographedon a silica column using a mixture of heptane and ethyl ether as theeluent to give 3.6 g of the expected product. M.p.=192° C.

Preparation 11:

5-Chloro-1,3-dihydro-3-spiro(4-tetrahydrothiopyran)indol-2-one

A--5-Chloro-1,3-dihydro-3,3-di(2-bromoethyl)-indol-2-one

7.66 g of bromine are added slowly to a mixture, cooled to about 0° C.,of 12.4 g of triphenylphosphine in 70 ml of DCM, and 4.58 g of5-chloro-1,3- dihydro-3,3-di2-(tetrahydropyran-2-yloxy)ethyl!indol-2-one, described in Table 2, arethen added. After 16 hours at RT, 60 ml of water are added and theorganic phase is separated off, washed with 60 ml of water and thendried over magnesium sulfate and evaporated under vacuum. The residue ischromatographed on a silica column using DCM as the eluent to give 3.12g of the expected product. M.p.=215° C.

B--5-Chloro-1,3-dihydro-3-spiro(4-tetrahydrothiopyran)indol-2-one

Under an inert atmosphere, 3 g of the product prepared in step A areadded to 3.2 ml of DMF and 2 g of sodium sulfide monohydrate and themixture is heated for 2 hours at 50° C. It is cooled to RT, 6 ml ofwater are added and the mixture is extracted with DCM. The organic phaseis washed with water, dried over magnesium sulfate and evaporated underreduced pressure. The oily residue obtained is purified bychromatography on silica using DCM as the eluent to give 2.02 g of theexpected compound.

NMR spectrum at 200 MHz in CDCl₃ :

8.12 ppm: s: 1H

7.2 ppm: m: 2H

6.8 ppm: d: 1H

3.25 ppm: m: 2H

2.65 ppm: m: 2H

2 ppm: m: 4H

Preparation 12:

5-Ethoxy-1,3-dihydro-3-spiro 4-tricyclo- 5.2.1.0²,6 !decane!indol-2-one

A mixture of 3 g of 5-ethoxy-1,3-dihydro-3-spiro 4-tricyclo 5.2.1.0²,6!dec-8-ene!indol-2-one, described in Table 2, and 1.5 g of 5%palladium-on-charcoal in 160 ml of MeOH is hydrogenated for 16 hours at40° C. under a pressure of 20 bar. The catalyst is filtered off onCeliteR and washed with MeOH and the filtrate is evaporated under vacuumto give 2.95 g of the expected product. M.p.=236° C.

Preparations 13 and 14:

5-Ethoxy-1,3-dihydro-3-spiro(4-methoxycyclohexane)indol-2-one, isomer Aand isomer B

A) 3-Methoxypentane-1,5-diol

25 ml of methyl trifluoromethylsulfonate are added to a solution of 30 gof diethyl 3-hydroxyglutarate and 33 ml of 2,6-di-tert-butylpyridine in500 ml of DCM and the mixture is refluxed for 5 hours. After cooling,500 ml of a 0.5N solution of HCl are added, the organic phase isdecanted and dried over magnesium sulfate and the solvent is evaporatedoff under vacuum. The solid obtained is taken up with 200 ml ofanhydrous THF, the mixture is filtered and the filtrate is then cooledto -5° C. 160 ml of a 1M solution of lithium aluminum hydride in THF arethen added slowly and the mixture is stirred for 16 hours, thetemperature being allowed to rise to RT. The reaction mixture is cooledto 0° C. and 5.5 ml of water, 18 ml of a 15% solution of NaOH and 5.5 mlof water are added successively. The mineral salts are filtered off andthe filtrate is evaporated under vacuum to give the expected productafter distillation under reduced pressure. B.p.=104° C. under 1.5 Pa.

B) 3-Methoxy-1,5-ditosyloxypentane

A solution of 31 g of p-toluenesulfonyl chloride and 26 ml oftriethylamine in 120 ml of THF is cooled to 0° C., 10 g of the compoundobtained in the previous step are added and the mixture is stirred for24 hours at RT. 120 ml of water are added to the reaction mixture, thesolvent is evaporated off under vacuum, the residue is extracted withAcOEt and dried over magnesium sulfate and the solvent is evaporated offunder vacuum. The oil obtained is taken up with 200 ml of ether and 200ml of 2N NaOH and the mixture is stirred for 16 hours at RT. Afterdecantation, the organic phase is dried over magnesium sulfate and thesolvent is evaporated off under vacuum to give 26 g of the expectedproduct after crystallization from cyclohexane. M.p.=58° C.

C) 5-Ethoxy-1,3-dihydro-3-spiro(4-methoxycyclohexane)indol-2-one, isomerA and isomer B

These compounds are prepared by the procedure described in Preparation 2starting from 11.85 g of 5-ethoxy-1,3-dihydroindol-2-one, 34 g ofpotassium tert-butylate and 26 g of the compound obtained in theprevious step. They are chromatographed on silica using acyclohexane/AcOEt mixture (80/20; v/v) as the eluent. The two isomersare separated into

the less polar isomer, A: compound of Preparation 13, m.p.=173° C.;

the more polar isomer, B: compound of Preparation 14, m.p.=186° C.

EXAMPLE 15-Chloro-1,3-dihydro-1-(3,4-dimethoxybenzyl)-3-spirocyclopentaneindol-2-one

66 mg of sodium hydride as an 80% dispersion in oil are added inportions to a solution of 440 mg of5-chloro-1,3-dihydro-3-spirocyclopentaneindol-2-one in 5 ml of DMF;after stirring for 30 minutes, 510 mg of1-bromomethyl-3,4-dimethoxybenzene are introduced and the mixture isthen stirred for 24 hours at RT. The solvent is evaporated off undervacuum and the residue is then extracted with ethyl acetate, washed withwater and dried over sodium sulfate. After evaporation of the solvents,the residue is chromatographed on silica using a DCM/AcOEt mixture(97/3; v/v) as the eluent to give 250 mg of the expected product.

NMR spectrum at 200 MHz in DMSO:

1.7-2.1 ppm: m: 8H

3.7 ppm: s: 6H

4.8 ppm: s: 2H

6.7 ppm: d of d: 1H

6.9 ppm: m: 3H

7.2 ppm: d of d: 1H

7.4 ppm: d: 1H

EXAMPLE 21,3-Dihydro-1-(2,4-dimethoxybenzyl)-3-spiro(N-methylpiperidine-4)indol-2-on

A solution of 2.08 g of 1-hydroxymethyl-2,4-dimethoxybenzene in 20 ml ofether is cooled to -10° C. under nitrogen and a solution of 0.4 ml ofphosphorus tribromide in 8 ml of ether is added dropwise; the resulting1-bromomethyl-2,4-dimethoxybenzene is kept at -30° C.

A solution of 1.78 g of1,3-dihydro-3-spiro(N-methylpiperidine-4)indol-2-one in 170 ml of THF iscooled to -50° C. under nitrogen, 0.970 g of potassium tert-butylate isadded and the temperature is allowed to rise to 0° C.; the mixture iscooled again to -50° C. and a further 1.380 g of potassium tert-butylateare added. After cooling to -70° C., the brominated derivative preparedabove is added and the temperature is then allowed to rise to RT. 20 mlof water are added, the solvents are concentrated under vacuum, theresidue is extracted with AcOEt and dried over sodium sulfate and thesolvent is evaporated off. The residue is chromatographed on silicausing a DCM/MeOH mixture (9/1; v/v) as the eluent. The expected productcrystallizes from pentane. m=1.260 g. M.p.=101° C.

EXAMPLE 31,3-Dihydro-1-(2,4-dimethoxybenzyl)-3-spiro(N-ethoxycarbonylpiperidine-4)indol-2-one

A solution of 1.152 g of ethyl chloroformate in 1.5 ml of benzene isbrought to the reflux point and a solution of 1.3 g of the compoundobtained in the previous Example in 10 ml of benzene is added dropwise.After refluxing for 6 hours, the solvent is evaporated off under vacuumand the residue is taken up with water. It is extracted with ethylacetate and washed with a 2N solution of hydrochloric acid and then withwater. The expected product crystallizes from iso ether.

m=1.12 g. M.p.=156° C.

EXAMPLE 45-Chloro-1,3-dihydro-1-(3,5-dimethoxybenzyl)-3-spirocyclohexaneindol-2-one

0.03 g of sodium hydride as an 80% dispersion in oil is added inportions to a solution of 0.236 g of5-chloro-1,3-dihydro-3-spirocyclohexaneindol-2-one in 5 ml of THF andthe mixture is stirred for 30 minutes. It is cooled in an ice bath,0.190 g of 1-chloromethyl-3,5-dimethoxybenzene is added slowly and thetemperature is then allowed to rise to RT. After refluxing for 5 hours,the solvent is evaporated off under vacuum and the residue is taken upwith water. It is extracted with ether, washed with water and dried oversodium sulfate, the solvents are evaporated off and the residue is thenchromatographed on silica using DCM/AcOEt (99/1; v/v) as the eluent. Theexpected product crystallizes from iso ether. m=0.044 g. M.p.=106° C.

EXAMPLE 5 Methyl4-(5-ethoxy-2,3-dihydro-2-oxo-3-spirocyclohexaneindol-1-yl)methyl-3-methoxybenzoate

0.33 g of sodium hydride as an 80% dispersion in oil is added to asolution of 5-ethoxy-l,3-dihydro-3-spirocyclohexaneindol-2-one in 20 mlof DMF, after which 2.85 g of methyl 4-bromomethyl-3-methoxybenzoate areintroduced. After stirring for 4 hours at RT, the solvent is evaporatedoff and the residue is taken up with water. It is extracted with DCM,washed with water and dried over sodium sulfate, the solvents areevaporated off and the residue is then chromatographed on silica using aDCM/AcOEt mixture (97.5/2.5; v/v) as the eluent. The expected productcrystallizes from heptane.

m=3.445 g. M.p.=142° C.

EXAMPLE 64-(5-Ethoxy-2,3-dihydro-2-oxo-3-spirocyclohexaneindol-1-yl)methyl-3-methoxybenzoicacid

A solution containing 847 mg of the compound prepared in the previousExample and 420 mg of lithium hydroxide monohydrate in 9 ml of MeOH, 9ml of THF and 3 ml of water is stirred for 4 hours at RT. It is dilutedwith water, acidified to pH 1 by the addition of 1N hydrochloric acid,extracted with DCM, washed with water and dried over sodium sulfate.After evaporation of the solvent, the expected product crystallizes fromether. m=745 mg. M.p.=215°-217° C.

EXAMPLE 7 5-Ethoxy-1,3-dihydro-1- 2-methoxy-4-N-(2-methylphenyl)carbamoyl!benzyl!-3-spirocyclohexaneindol-2-one

A)4-(5-Ethoxy-2,3-dihydro-2-oxo-3-spirocyclohexaneindol-1-yl)methyl-3-methoxybenzoylchloride

A solution of 2.1 g of the acid prepared in the previous Example in 20ml of thionyl chloride is refluxed for 2 hours. It is evaporated undervacuum and the residue is taken up with toluene and then concentrated.The oily residue obtained is used as such in the next step.

B) 5-Ethoxy-,1,3-dihydro-1- 2-methoxy-4-N-(2-methylphenyl)carbamoyl!benzyl!-3-spirocyclohexaneindol-2-one

A solution containing 860 mg of the acid chloride prepared in theprevious step, 0.2 ml of 2-methylaniline and 2 ml of TEA in 80 ml of DCMis stirred for 24 hours at RT. It is washed successively with water,with 1N HCl, with water, with a saturated solution of NaHCO₃ and thenwith water. After drying over sodium sulfate and evaporation of thesolvents, the residue is chromatographed on silica using DCM/acetone(98/2; v/v) as the eluent. The expected product crystallizes from MeOH.m=0.082 g. M.p.=168° C.

EXAMPLE 85-Ethoxy-1,3-dihydro-1-(2-methoxy-4-nitrobenzyl)-3-spirocyclohexaneindol-2-one

0.66 g of sodium hydride as an 80% dispersion in oil is added inportions to a solution of 4.9 g of5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-2-one in 40 ml of DMF.After stirring for 15 minutes, 5.4 g of1-bromomethyl-2-methoxy-4-nitrobenzene are introduced and the mixture isstirred for 24 hours at RT. The solvent is evaporated off under vacuumand the residue is then taken up with water, extracted with DCM, washedwith water and dried over sodium sulfate. After evaporation of thesolvent, the residue is chromatographed on silica using DCM/AcOEt (98/2;v/v) as the eluent to give the expected product, which is taken up withMeOH and filtered off. m=6.7 g. M.p.=170° C.

EXAMPLE 95-Ethoxy-1,3-dihydro-1-(2-methoxy-4-aminobenzyl)-3-spirocyclohexaneindol-2-one

A mixture of 6.157 g of the compound prepared in the previous Exampleand a few grams of Raney® nickel in 270 ml of 95° ethanol ishydrogenated for 24 hours at RT under a pressure of 50 bar. The reactionmedium is filtered on Celite®, the material on the filter is washed withDCM and the solvents are then evaporated off under vacuum. The expectedproduct crystallizes from MeOH. m=4.1 g. M.p.=81° C.

EXAMPLE 10 5-Ethoxy-1,3-dihydro-1-4-(Δ3-pyrrolin-1-yl)-2-methoxybenzyl!-3-spirocyclohexaneindol-2-one

1.52 g of the compound prepared in the previous Example, 1.05 g ofcis-1,4-dichlorobut-2-ene and 1.74 ml of TEA are mixed with 35 ml of DMFand the mixture is refluxed for 30 minutes. The solvent is evaporatedoff under vacuum and the residue is taken up with water and thenextracted with AcOEt, washed with water and dried over sodium sulfate.After evaporation of the solvent, the residue is chromatographed onsilica using DCM/MeOH (98/2; v/v) as the eluent. The expected compoundcrystallizes from iso ether. m=0.835 g. M.p.=114° C.

EXAMPLE 111-(4-Dimethylamino-2-methoxybenzyl)-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-2-one

420 mg of the compound prepared in Example 9 and 4 ml of 37%formaldehyde are mixed with 10 ml of acetonitrile; 0.5 g of sodiumcyanoborohydride and 0.15 ml of AcOH are added and the mixture is thenstirred for 48 hours. After evaporation of the solvent, the residue istaken up with water and then extracted with AcOEt and dried over sodiumsulfate. The solvent is evaporated off and the residue is thenchromatographed on silica using DCM/AcOEt (90/10; v/v) as the eluent.The expected compound crystallizes from heptane. m=0.29 g. M.p.=138° C.

EXAMPLE 12 5-Ethoxy-1-4-(2-ethylbutyroylamino)-2-methoxybenzyl!-1,3-dihydro-3-spirocyclohexaneindol-2-one

420 mg of the compound prepared in Example 9 and 1.65 ml of TEA areplaced in 20 ml of DCM, 0.5 g of 2-ethylbutyroyl chloride is addedslowly and the mixture is stirred for 2 hours at RT. The organic phaseis washed with water, dried over sodium sulfate and evaporated undervacuum. The residue is chromatographed on silica using DCM/MeOH (99/1;v/v) as the eluent. The expected product crystallizes from a pentane/isoether mixture. m=0.30 g. M.p.=119° C.

EXAMPLE 131-(4-Diethylaminoacetylamino-2-methoxybenzyl)-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-2-one

A)1-(4-Chloroacetylamino-2-methoxybenzyl)-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-2-one

A solution of 420 mg of the compound prepared in Example 9 and 1 ml ofTEA in 12.5 ml of DCM is prepared, 0.27 ml of chloroacetyl chloride isadded and the mixture is stirred for 2 hours. After washing with water,it is dried over sodium sulfate, the solvents are evaporated off and theresidue is then chromatographed on silica using DCM/MeOH (98/2; v/v) asthe eluent. The expected product crystallizes from iso ether. m=0.36 g.M.p.=204° C.

B)1-(4-Diethylaminoacetylamino-2-methoxybenzyl)-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-2-one

A solution containing 340 mg of the compound prepared in the previousstep and 7 ml of diethylamine in 15 ml of THF is stirred for 48 hours atRT. The solvent is evaporated off under vacuum and the residue is thenchromatographed on silica using DCM/MeOH (98/2; v/v) as the eluent. Theexpected product crystallizes from a pentane/iso ether mixture. m=0.165g. M.p.=75° C.

EXAMPLE 14 5-Ethoxy-1,3-dihydro-1-2-methoxy-4-(orthomethylbenzamido)benzyl!-3-spirocyclohexaneindol-2-one

A solution containing 285 mg of the compound prepared in Example 9, 0.1ml of ortho-methylbenzoyl chloride and 0.75 mg of TEA in 30 ml of DCM isstirred for 24 hours at RT. It is washed with water and dried oversodium sulfate, the solvent is evaporated off and the residue is thenchromatographed on silica using DCM/MeOH (99.5/0.5; v/v) as the eluent.The expected product crystallizes from iso ether. m=285 mg. M.p.=158° C.

EXAMPLE 155-Chloro-1,3-dihydro-1-(2-methoxy-4-nitrobenzyl)-3-spirocyclohexaneindol-2-one

0.528 g of sodium hydride as an 80% dispersion in oil is added inportions to a solution of 4.434 g of5-chloro-1,3-dihydro-3-spirocyclohexaneindol-2-one in 40 ml of DMF. Themixture is cooled in an ice bath, 5.4 g of1-bromomethyl-2-methoxy-4-nitrobenzene are then added slowly and themixture is stirred for 24 hours at RT. It is extracted with ether,washed with water and dried over sodium sulfate and the solvent is thenconcentrated. The residue is chromatographed on silica using DCM as theeluent. The expected product crystallizes from methanol. m=6.13 g.M.p.=180° C.

EXAMPLE 161-(4-Amino-2-methoxybenzyl)-5-chloro-1,3-dihydro-3-spirocyclohexaneindol-2-one

A mixture of 5.8 g of the compound prepared in the previous Example anda few grams of Raney® nickel in 250 ml of 95° ethanol is hydrogenatedfor 24 hours at RT under a pressure of 50 bar. The catalyst is filteredoff on Celite® and the filtrate is then evaporated under vacuum. Theexpected product crystallizes from methanol. m=3.25 g. M.p.=88° C.

EXAMPLE 175-Chloro-1,3-dihydro-1-(4-phenoxycarbonylamino-2-methoxybenzyl)-3-spirocyclohexaneindol-2-one

740 mg of the compound prepared in the previous Example are placed in 25ml of THF, 210 mg of sodium hydroxide in 1.7 ml of water are added, themixture is cooled to about 5°-10° C. and 0.9 ml of phenyl chloroformatein 25 ml of THF is then added dropwise. The mixture is stirred for 2hours at RT. The solvent is evaporated off and the residue is taken upwith water and then extracted with ether and washed with water. Afterdrying over sodium sulfate and evaporation of the solvent, the residueis chromatographed on silica using a DCM/MeOH mixture (98/2; v/v) as theeluent. The expected product crystallizes from ethanol. m=0.63 g.M.p.=196° C.

EXAMPLE 18 5-Chloro-1,3-dihydro-1-2-methoxy-4-(N'-methylureido)benzyl!-3-spirocyclohexaneindol-2-one

A solution of 0.30 g of the compound prepared in Example 16 in 20 ml ofDCM is cooled to 0° C. and 0.05 ml of methyl isocyanate is added. Afterstirring for 24 hours at RT, the mixture is washed with water, driedover sodium sulfate and evaporated under vacuum. The residue ischromatographed on silica using DCM/MeOH (98/2; v/v) as the eluent. Theexpected compound crystallizes from iso ether. m=0.280 g. M.p.=230° C.

EXAMPLE 19 5-Chloro-1,3-dihydro-1-4-(3,4-dimethoxybenzenesulfonylamino)-2-methoxybenzyl!-3-spirocyclohexaneindol-2-one

200 mg of 3,4-dimethoxybenzenesulfonyl chloride are added to a solutionof 280 mg of the compound prepared in Example 16 in 10 ml of pyridineand the mixture is stirred for 24 hours at RT. The solvent is evaporatedoff under vacuum and the residue is then taken up with water. It isextracted with DCM, washed with 1N hydrochloric acid and then withwater, dried over sodium sulfate and evaporated under vacuum. Theexpected compound crystallizes from ethanol. m=0.31 g. M.p.=180° C.EXAMPLE 20

5-Chloro-1,3-dihydro-1-(4-dimethylaminosulfonamido-2-methoxybenzyl)-3-spirocyclohexaneindol-2-one

A solution containing 371 mg of the compound prepared in Example 16 and0.12 ml of dimethylaminosulfamoyl chloride in 10 ml of pyridine isstirred for 72 hours. The solvent is evaporated off and the residue istaken up with water and then extracted with ether and washed with 1Nhydrochloric acid and with water. After drying over sodium sulfate andevaporation of the solvent, the residue is chromatographed on silicausing a DCM/MeOH mixture (99.4/0.6; v/v) as the eluent. The expectedproduct crystallizes from iso ether. m=0.160 g. M.p.=164° C.

EXAMPLE 21 5-Chloro-1-4-(N',N'-diethylureido)-2-methoxybenzyl!-1,3-dihydro-3-spirocyclohexaneindol-2-one

1.64 ml of diethylamine are added to a solution of 295 mg of thecompound prepared in Example 17 in 20 ml of EtOH and 5.5 ml of DCM andthe mixture is stirred for 24 hours at RT. The solvents are evaporatedoff under vacuum and the residue is chromatographed on silica using aDCM/MeOH mixture (99/1; v/v) as the eluent. The expected product istaken up with heptane and filtered off. m=0.235 g. M.p.=108° C.

The compounds according to the invention described in Table 3 below wereprepared using the procedures described above.

                                      TABLE 3                                     __________________________________________________________________________     ##STR40##                                                                    N.sup.o Ex.                                                                        R.sub.1                                                                            CR.sub.3 R.sub.4                                                                         R.sub.5                                                                            R.sub.6    M.p. °C. or                       __________________________________________________________________________                                         NMR                                      22 (a)                                                                             H    cyclohexane                                                                              3-MeO                                                                              MeO        106                                      23 (b)                                                                             H    4-piperidine                                                                             2-MeO                                                                              MeO        NMR                                      24 (c)                                                                             Cl   cyclohexane                                                                              H    MeO         80                                      25 (d)                                                                             Cl   cyclohexane                                                                              2-MeO                                                                              MeO        106                                      26 (d)                                                                             Cl   4,4-dimethylcyclohexane                                                                  2-MeO                                                                              MeO        141                                      27 (a)                                                                             Cl   cyclohexane                                                                              3-MeO                                                                              MeO        117                                      28 (d)                                                                             MeO  cyclohexane                                                                              2-MeO                                                                              MeO        124                                      29 (a)                                                                             MeO  cyclohexane                                                                              3-MeO                                                                              MeO        110                                      30 (a)                                                                             EtO  cyclohexane                                                                              3-MeO                                                                              MeO         88                                      31 (e)                                                                             EtO  cyclohexane                                                                              2-MeO                                                                              tBuNHCO    187                                      32 (f)                                                                             Cl   cyclohexane                                                                              H    F.sub.3 C   90                                      33 (g)                                                                             H    cyclohexane                                                                              H    O.sub.2 N  118                                      34 (g)                                                                             Cl   cyclohexane                                                                              H    O.sub.2 N  139                                      35 (h)                                                                             Cl   cyclohexane                                                                              2-Me O.sub.2 N  144                                      36 (i)                                                                             Cl   cyclohexane                                                                              3-MeO                                                                              O.sub.2 N   80                                      37 (g)                                                                             MeO  cyclohexane                                                                              H    O.sub.2 N  106                                      38 (h)                                                                             MeO  cyclohexane                                                                              2-Me O.sub.2 N  133                                      39 (j)                                                                             MeO  cyclohexane                                                                              2-MeO                                                                              O.sub.2 N  200                                      40 (j)                                                                             EtO  4,4-dimethylcyclohexane                                                                  2-MeO                                                                              O.sub.2 N  106                                      41 (k)                                                                             Cl   cyclohexane                                                                              H    H.sub.2 N  136                                      42 (k)                                                                             Cl   cyclohexane                                                                              2-Me H.sub.2 N  157                                      43 (k)                                                                             Cl   cyclohexane                                                                              3-MeO                                                                              H.sub.2 N  113                                      44 (k)                                                                             MeO  cyclohexane                                                                              H    H.sub.2 N  192                                      45 (k)                                                                             MeO  cyclohexane                                                                              MeO  H.sub.2 N  165                                      46 (l)                                                                             Cl   cyclohexane                                                                              2-MeO                                                                              MeCONH     194                                      47 (l)                                                                             Cl   cyclohexane                                                                              2-MeO                                                                              C.sub.6 H.sub.11 CONH                                                                    143                                      48 (l)                                                                             Cl   cyclohexane                                                                              2-MeO                                                                               ##STR41## 190                                      49 (l)                                                                             Cl   cyclohexane                                                                              2-MeO                                                                               ##STR42## 205                                      50 (l)                                                                             MeO  cyclohexane                                                                              2-MeO                                                                              MeCONH     202                                      51 (l)                                                                             MeO  cyclohexane                                                                              H                                                                                   ##STR43## 167                                      52 (l)                                                                             MeO  cyclohexane                                                                              2-MeO                                                                               ##STR44## 157                                      53 (m)                                                                             Cl   cyclohexane                                                                              H    PhOCONH    186                                      54 (m)                                                                             Cl   cyclohexane                                                                              3-MeO                                                                              PhOCONH    112                                      55 (n)                                                                             Cl   cyclohexane                                                                              H    Et.sub.2 NCONH                                                                           190                                      56 (n)                                                                             Cl   cyclohexane                                                                              3-MeO                                                                              Et.sub.2 NCONH                                                                           108                                      57 (o)                                                                             Cl   cyclohexane                                                                              2-Me MeNHCONH   153                                      58 (n)                                                                             EtO  cyclohexane                                                                              2-MeO                                                                              Et.sub.2 NCONH                                                                           131                                      59 (p)                                                                             EtO  cyclohexane                                                                              2-MeO                                                                               ##STR45## 133                                      60 (d)                                                                             Cl   N-methyl-4-piperidine                                                                    2-MeO                                                                              MeO         64                                      61 (m)                                                                             EtO  cyclohexane                                                                              2-MeO                                                                              PhOCONH    170                                      62 (j)                                                                             EtO                                                                                 ##STR46## 2-MeO                                                                              O.sub.2 N   88                                      63 (q)                                                                             EtO                                                                                 ##STR47## 2-MeO                                                                              H.sub.2 N   96                                      64 (r)                                                                             EtO                                                                                 ##STR48## 2-MeO                                                                              Et.sub.2 NCONH                                                                           126                                      65 (j)                                                                             EtO  4-tetrahydropyrane                                                                       2-MeO                                                                              O.sub.2 N  163                                      66 (s)                                                                             EtO  4-tetrahydropyrane                                                                       2-MeO                                                                              H.sub.2 N  171                                      67 (r)                                                                             EtO  4-tetrahydropyrane                                                                       2-MeO                                                                              Et.sub.2 NCONH                                                                            98                                      68 (1) (j)                                                                         EtO  4-methoxycyclohexane                                                                     2-MeO                                                                              O.sub.2 N  oil                                      69 (1) (s)                                                                         EtO  4-methoxycyclohexane                                                                     2-MeO                                                                              H.sub.2 N   92                                      70 (1) (r)                                                                         EtO  4-methoxycyclohexane                                                                     2-MeO                                                                              Et.sub.2 NCONH                                                                            62                                      __________________________________________________________________________

NMR spectrum for Example 23 at 200 MHz in DMSO:

1.6-1.9 ppm: m: 4H

2.9-3.3 ppm: m: 4H

3.8 ppm: s: 3H

3.9 ppm: s: 3H

4.8 ppm: s: 2H

6.5 ppm: d of d: 1H

6.65 ppm: d: 1H

6.85 ppm: d: 1H

6.95 ppm: d: 1H

7.1 ppm: t: 1H

7.25 ppm: t: 1H

7.6 ppm: d: 1H

(a) This compound is prepared by the procedure described in EXAMPLE 1.

(b) This compound is prepared by the following procedure: A mixture of0.79 g of the compound obtained in EXAMPLE 3 and 1.4 g of KOH in 5 ml of95° EtOH is refluxed for 4 hours. After cooling, water is added, themixture is extracted with ether, the organic phase is extracted with a3N solution of HCl, the acidic aqueous phase is rendered basic by theaddition of a 10% solution of NaOH, extracted with ether, washed withwater and dried over sodium sulfate and the solvent is evaporated offunder vacuum. The residue is chromatographed on silica using a DCM/MeOHmixture (80/20; v/v, then 50/50; v/v) as the eluent to give 0.31 g ofthe expected product.

(c) This compound is prepared by the procedure described in EXAMPLE 1using 1-chloromethyl-4-methoxybenzene.

(d) This compound is prepared by the procedure described in EXAMPLE 2.

(e) This compound is prepared by the following procedure: A mixture of0.6 g of the compound obtained in EXAMPLE 6, 1 ml of tert-butylamine,0.73 g of BOP, 2 ml of DIPEA and 45 ml of DCM is stirred for 1 hour atRT. It is washed with a 1N solution of HCl, with water, with a saturatedsolution of NaHCO₃ and with water and dried over Na₂ SO₄ and the solventis evaporated off under vacuum. The residue is chromatographed on silicausing a DCM/MeOH mixture (98/2; v/v) as the eluent to give 0.295 g ofthe expected product after crystallization from iso ether.

(f) This compound is prepared by the procedure described in EXAMPLE 1starting from 1-bromomethyl-4-trifluoromethylbenzene.

(g) This compound is prepared by the procedure described in EXAMPLE 8starting from 1-bromomethyl-4-nitrobenzene.

(h) This compound is prepared by the procedure described in EXAMPLE 8starting from 1-bromomethyl-2-methyl-4-nitrobenzene.

(i) This compound is prepared by the procedure described in EXAMPLE 8starting from 1-bromomethyl-3-methoxy-4-nitrobenzene.

(j) This compound is prepared by the procedure described in EXAMPLE 8.

(k) This compound is prepared by the procedure described in EXAMPLE 9starting from the corresponding nitro compound.

(l) This compound is prepared by the procedure described in EXAMPLE 12starting from the corresponding amino compound and using the appropriateacid chlorides.

(m) This compound is prepared by the procedure described in EXAMPLE 17starting from the corresponding amino compound.

(n) This compound is prepared by the procedure described in EXAMPLE 21starting from the corresponding phenoxycarbonylamino compound.

(o) This compound is prepared by the procedure described in EXAMPLE 18starting from the corresponding amino compound.

(p) This compound is prepared by the procedure described in EXAMPLE 21starting from the corresponding phenoxycarbonylamino compound and usingpiperidine.

(q) This compound is prepared by the following procedure: A mixture of1.26 g of the compound of EXAMPLE 62 and 1.37 g of tin powder in 15 mlof EtOH is cooled to 10° C., 2.73 ml of concentrated HCl are added andthe mixture is then heated at 40° C. for 1 hour. After cooling, asaturated solution of NaHCO₃ is added, the mixture is extracted withAcOEt and dried over Na₂ SO₄ and the solvent is evaporated off undervacuum. The residue is chromatographed on silica using DCM as the eluentto give 0.93 g of the expected product.

(r) This compound is prepared by the procedures described in EXAMPLE 17and then in EXAMPLE 21.

(s) This compound is prepared by the procedure described in note (q)above.

(1) This compound is prepared from the compound obtained in Preparation14 (isomer B: the more polar compound).

(2) This compound is prepared from the compound of EXAMPLE 68.

(3) This compound is prepared from the compound of EXAMPLE 69.

What is claimed is:
 1. A compound of the formula: ##STR49## in which: R₁and R₂ are each independently a hydrogen; a halogen; a hydroxyl; anω-halogeno(C₁ -C₇)alkoxy; a (C₁ -C₇)alkyl; a trifluoromethyl; a (C₁-C₇)alkoxy; a polyhalogeno(C₁ -C₇)alkoxy; an ω-hydroxy(C₂ -C₇)alkoxy; anω-methoxy(C₂ -C₇)alkoxy; an ω-amino(C₂ -C₇)alkoxy which is free orsubstituted by one or two (C₁ -C₇)alkyls; a (C₃ -C₇)cycloalkoxy; a (C₃-C₇)cycloalkylmethoxy; a phenoxy; a benzyloxy; a (C₁ -C₇)alkylthio; aphenylthio; a nitro; an amino which is free or substituted by one or two(C₁ -C₇)alkyls; a cyano; a formyl; a (C₁ -C₇)alkylcarbonyl; a benzoyl; aformyloxy; a (C₁ -C₇)alkylcarbonyloxy; a benzoyloxy; a (C₁-C₇)alkylsulfonamido; a phenylsulfonamido; a benzylsulfonamido; a (C₁-C₇)alkylcarbonyl-amino; a (C₁ -C₇)alkoxycarbonylamino; a ureido whichis unsubstituted or substituted by a phenyl, a benzyl or one or two (C₁-C₇)alkyls; or a thioureido which is unsubstituted or substituted by aphenyl, a benzyl or one or two (C₁ -C₇)alkyls, with the proviso that R₁and R₂ are not simultaneously hydrogen;R₃ and R₄ together form a group--(CH₂)_(p) X(CH₂)_(q) --; or R₃ and R₄, together with the carbon towhich they are bonded, form an optionally fused, saturated orunsaturated C₃ -C₁₂ hydrocarbon ring which is unsubstituted orsubstituted by one or more (C₁ -C₇)alkyl groups, by a (C₃-C₅)spirocycloalkyl, by an oxo group or by one or two hydroxyl groups,said hydroxyl group(s) being unsubstituted or substituted by a groupselected from the group consisting of a (C₁ -C₄)alkyl, a (C₁-C₂)alkoxy(C₁ -C₄)alkyl, a phenyl(C₁ -C₂)alkoxy(C₁ -C₄)alkyl, atetra-hydrofuranyl and a tetrahydropyranyl; R₅ is hydrogen or has one ofthe meanings designated for R₆ ; R₆ is a halogen; a (C₁ -C₇)alkyl; atrifluoromethyl; a cyano; a nitro; a hydroxylamino; a hydroxyl; acarboxyl; a guanidino which is unsubstituted or substituted in the1-position by a (C₁ -C₇)alkyl and/or in the 3-position by one or two (C₁-C₇)alkyls, a phenyl or a benzyl and/or in the 2-position by a cyano; agroup --OR₇ ; a group --SR₇ ; a formyl; a (C₁ -C₇)alkylcarbonyl; abenzoyl; a (C₁ -C₇)alkoxycarbonyl; a phenoxycarbonyl; abenzyloxycarbonyl; a group --CONR₁₇ R₁₈ ; a group --CSNR₁₁ R₁₉ ; a group--SO₂ NR₂₀ R₂₁ ; a (C₁ -C₇)alkyl-sulfonamido; a group --NHSO₂ --Ar; abenzylsulfonamido; an aminosulfonamido in which the amino is free orsubstituted by R₁₆ and R₂₂ ; a group --NR₈ R₉ ; a group --CO--NH--CR₁₀R₂₃ --COR₁₂ ; or a group --CH₂ NR₈ R₉ ; R₇ is a (C₁ -C₇)alkyl; a phenyl;a benzyl; a (C₃ -C₇)cycloalkyl; a (C₂ -C₇)alkenyl; an ω-halogeno(C₂-C₇)alkyl; a polyhalogeno(C₁ -C₇)alkyl; an ω-hydroxy(C₂ -C₇)alkyl; aformyl; a (C₁ -C₇)alkylcarbonyl; a benzoyl; an ω-carboxy(C₁ -C₇)alkyl;an ω-(C₁ -C₇)alkoxycarbonyl(C₁ -C₇)alkyl; an ω-benzyloxycarbonyl(C₁-C₇)alkyl; an ω-amino(C₂ -C₇)alkyl in which the amino group is free orsubstituted by one or two (C₁ -C₇)alkyls, or in the form of an ammoniumion; or an ω-carbamoyl(C₁ -C₇)alkyl in which the carbamoyl is free orsubstituted by one or two (C₁ -C₇)alkyls; R₈ and R₉ are eachindependently a hydrogen; a (C₁ -C₇)alkyl; or a group --CH₂ --Ar; R₉ canalso be a group Ar; a (C₃ -C₈)alkenyl; a formyl; a (C₁-C₇)alkylcarbonyl; a (C₁ -C₇)alkylthiocarbonyl; a (C₃-C₇)cycloalkylcarbonyl; a (C₃ -C₇)cycloalkylthiocarbonyl; an ω-amino(C₂-C₇)alkylcarbonyl in which the amino is free or substituted by one ortwo (C₁ -C₇)alkyls; an ω-hydroxy(C₁ -C₇)alkylcarbonyl; an ω-benzyloxy(C₁-C₇)alkylcarbonyl; a pyridylcarbonyl; a methylpyridylcarbonyl; athienylcarbonyl; a group --CO--Ar; a group --CO--CH₂ --Ar; a (C₁--C₇)alkoxycarbonyl; a phenoxycarbonyl; a phenoxythiocarbonyl; abenzyloxy-carbonyl; a group --CO--CR₁₀ R₂₃ --NR₁₁ R₁₉ ; a group --CR₁₀R₂₃ COR₁₂ ; a group --(CH₂)_(t) COR₁₂ ; a group --CO(CH₂)_(u) COR₁₂ ; agroup --CONR₁₄ R₂₄ ; a group --CSNR₁₄ R₂₄ ; or a heterocyclic radicalselected from pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl,pyridazinyl, pyrimidinyl and thiazolyl; --or else R₈ and R₉, togetherwith the nitrogen atom to which they are bonded, form hydantoin;N-methylhydantoin; or a heterocyclic radical selected from pyrrol-1-yl,A,3-pyrrolin-1-yl, pyrrolidin-1-yl and isoindolin-2-yl in which thebenzene ring is unsubstituted or substituted by a halogen, a (C₁-C₇)alkyl, a trifluoromethyl or a methoxy; R₁₀ and R₂₃ are eachindependently hydrogen; a (C₁ -C₇)alkyl; or a benzyl; or R₁₀ and R₂₃,together with the carbon atom to which they are bonded, form a (C₃-C₇)cycloalkyl; R₁₁ and R₁₉ are each independently hydrogen; or a (C₁-C₇)alkyl; R₁₂ is a hydroxyl; a (C₁ -C₇)alkoxy; or an amino which isfree or substituted by one or two (C₁ -C₇)alkyls; R₁₃ is hydrogen; a (C₁-C₇)alkyl; a phenyl; a benzyl; a formyl; a (C₁ -C₇)alkylcarbonyl; abenzoyl; a (C₁ -C₇)alkoxycarbonyl; or a carbamoyl which is unsubstitutedor substituted by one or two (C₁ -C₇)alkyls; R₁₄ and R₂₄ are eachindependently hydrogen; or a (C₁ -C₇)alkyl; R₂₄ can also be a (C₁-C₇)alkyl substituted by R₁₅ ; a group Ar; a (C₃ -C₇)cycloalkyl; or anadamantyl; or R₁₄ and R₂₄, together with the nitrogen atom to which theyare bonded, form a heterocycle selected from morpholine, thiomorpholine,piperazine, azetidine, pyrrolidine, piperidine and perhydroazepine, saidheterocycle being unsubstituted or substituted by one or more methylgroups, a phenyl or an amino group which is free or carries a protectinggroup; R₁₅ is a group Ar; a pyridyl; a hydroxyl; a (C₁ -C₇)alkoxy; agroup --NR₁₁ R₁₉ ; a carboxyl; or a (C₁ -C₇)alkoxycarbonyl; R₁₆ and R₂₂are each independently a hydrogen; or a (C₁ -C₇)alkyl; or R₁₆ and R₂₂,together with the nitrogen atom to which they are bonded, form aheterocycle selected from azetidine. pyrrolidine, piperidine, piperazineand perhydroazepine, said heterocycle being unsubstituted or substitutedby one or more methyl groups; R₁₇ and R₁₈ are each independentlyhydrogen; or a (C₁ -C₈)alkyl; R₁₈ can also be a (C₃ -C₇)cycloalkyl whichis unsubstituted or substituted by a (C₁ -C₄)alkyl; a group Ar; apyridyl; a methylpyridyl; a piperid-4-yl substituted in the 1-positionby R₂₇ ; a piperid-1-yl; a pyrrolidin-1-yl; a morpholin-4-yl; or a (C₁-C₇)alkyl substituted by one or more halogens or by R₂₆ ; or else R₁₇and R₁₈, together with the nitrogen atom to which they are bonded, forma heterocyclic radical R₂₅ ; R₂₀ and R₂₁ are each independentlyhydrogen; or a (C₁ -C₇)alkyl; or else R₂₀ and R₂₁, together with thenitrogen atom to which they are bonded, form a heterocyclic radical R₂₅; R₂₅ is a morpholin-4-yl; a thiomorpholin-4-yl; an azetidin-1-yl whichis unsubstituted or substituted in the 3-position by a group --NR₁₁ R₁₉,a (C₁ -C₇)alkyl, a phenyl, a benzyl, or a (C₁ -C₇)alkylcarbonyl; aperhydroazepin-1-yl; a piperazin-1-yl which is unsubstituted orsubstituted in the 4-position by a (C₁ -C₇)alkyl, a phenyl, a benzyl, a(C₁ -C₇)alkylcarbonyl, a (C₁ -C₇)alkoxycarbonyl or a benzyloxycarbonyl;a piperid-1-yl which is unsubstituted or substituted in the 4-positionby a (C₁ -C₇)alkyl, a phenyl, a benzyl, a (C₁ -C₇)alkylcarbonyl or agroup --NR₁₁ R₁₉ ; or a pyrrolidin-1-yl which is unsubstituted orsubstituted by a (C₁ -C₇)alkyl, a phenyl, a benzyl, a (C₁-C₇)alkylcarbonyl, a hydroxymethyl, a carboxyl, a (C₁ -C₇)alkoxycarbonylor a carbamoyl which is unsubstituted or substituted by one or two (C₁-C₇)alkyls; R₂₆ is a hydroxyl; a (C₁ -C₇)alkoxy; a cyano; a carboxyl; a(C₁ -C₇)alkoxycarbonyl; a benzyloxycarbonyl; a group --NR₁₁ R₁₉ ; acarbamoyl which is free or substituted by one or two (C₁ -C₇)alkyls; apyrrolidin-1-ylcarbonyl; a piperid-1-ylcarbonyl; aperhydroazepin-1-ylcarbonyl; a group Ar; a (C₃ -C₇)cycloalkyl; anadamantyl; or a heterocyclic radical selected from a pyridyl, amethylpyridyl, a furanyl, a tetrahydrofuranyl, a thienyl, amethylthienyl, a pyrrolidin-1-yl, a piperid-1-yl and aperhydroazepin-1-yl; R₂₇ is a hydrogen; a (C₁ -C₇)alkyl; a phenyl; abenzyl; a formyl; a (C₁ -C₇)alkylcarbonyl; a benzoyl; a (C₁-C₇)alkoxycarbonyl; a phenoxycarbonyl; or a carbamoyl which is free orsubstituted by one or two (C₁ -C₇)alkyls; Ar is a phenyl which isunsubstituted or monosubstituted or polysubstituted by a substituentselected from a halogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, ahydroxyl, a (C₁ -C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a nitro, a cyano, an amino, a (C₁ -C₇)alkylaminoand a (C₁ -C₇)dialkylamino, said substituents being identical ordifferent; m is 1, 2, 3 or 4, provided that when m is 2, 3 or 4 each R₆independently represents a halogen, a (C₁ -C₇)alkyl or a (C₁ -C₇)alkoxy;p and q are each an integer, it being possible for their sum to varyfrom 3 to 6; t is an integer which can vary from 2 to 5; u is an integerwhich can vary from 0 to 3; X is oxygen, a group --NR₁₃, a group--N(O)R₁₃ or a group S(O)_(x) ; and x is 0, 1 or2;provided that at leastone of --CR₃ R₄, R₅ and R₆ contains one or more heterocyclic radicals;and its salts.
 2. A compound according to claim 1 wherein R₁ is in the5-position of the 1,3-dihydroindol-2-one and R₂ is hydrogen.
 3. Acompound according to claim 1 wherein R₁ is a chlorine or fluorine atomor an ethoxy group in the 5-position of the 1,3-dihydroindol-2-one andR₂ is hydrogen.
 4. A compound according to claim 1 wherein R₃ and R₄,together with the carbon to which they are bonded, form a C₃ -C₁₂hydrocarbon ring.
 5. A compound according to claim 1 wherein R₃ and R₄,together with the carbon to which they are bonded, form a cycloheptane,an adamantane, a tricyclo 5.2.1.0²,6 !decane, a tricyclo 5.2.1.0²,6!dec-8-ene, a bicyclo 2.2.1!heptane, a bicyclo 3.3.1!nonane or acyclohexane which is unsubstituted or substituted by a C₃ -C₅-spirocycloalkyl, by one or two C₁ -C₇ -alkyls or by a C₁ -C₄ -alkoxy.6. A compound according to claim 1 wherein R₅ is either hydrogen or amethoxy group in the 2-position and R₆ in the 4-position is a groupselected from:a methoxy; a (C₁ -C₇)alkylcarboxamido; a group --NHCO--Ar;a group --CONR₁₇ R₁₈ ; and a group --NR₈ CONR₁₄ R₂₄,in which Ar, R₁₇,R₁₈, R₈, R₁₄ and R₂₄ are as defined for (I) in claim
 1. 7. Apharmaceutical composition containing (i) an effective amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof and (ii) suitable excipients.
 8. A compound according to claim 1of formula (I), in which:R₁ and R₂ are each independently a hydrogen; ahalogen; a hydroxyl; an halogeno(C₁ -C₇)alkoxy; a (C₁ -C₇)alkyl; atrifluoromethyl; a (C₁ -C₇)alkoxy; a polyhalogeno(C₁ -C₇)alkoxy; anω-hydroxy(C₂ -C₇)alkoxy; an ω-methoxy(C₂ -C₇)alkoxy; or an ω-amino(C₂-C₇)alkoxy which is free or substituted by one or two (C₁ -C₇)alkyls; a(C₃ -C₇)cycloalkoxy; a (C₃ -C₇)cycloalkylmethoxy; with the proviso thatR₁ and R₂ are not simultaneously hydrogen; R₃ and R₄ together form agroup --(CH₂)_(p) X(CH₂)_(q) --; or R₃ and R₄, together with the carbonto which they are bonded, form an optionally fused, saturated orunsaturated C₃ -C₁₂ hydrocarbon ring which is unsubstituted orsubstituted by one or more (C₁ -C₇)alkyl groups, by a (C₃-C₅)spirocycloalkyl, by an oxo group or by one or two hydroxyl groups,said hydroxyl group(s) being unsubstituted or substituted by a groupselected from the group consisting of a (C₁ -C₄)alkyl, a (C₁-C₂)alkoxy(C₁ -C₄)alkyl, a phenyl(C₁ -C₂)alkoxy(C₁ -C₄)alkyl, atetrahydrofuranyl and a tetrahydropyranyl; R₅ is hydrogen or a group--OR₇ ; R₆ is a halogen; a nitro; a group --OR₇ ; a group --SR₇ ; agroup --NR₈ R₉ ; a group --CONR₁₇ R₁₈ or a group --CH₂ NR₈ R₉ ; R₇ is a(C₁ -C₇)alkyl; a (C₃ -C₇)cycloalkyl; an ω-halogeno(C₂ -C₇)alkyl; apolyhalogeno(C₁ -C₇)alkyl; an ω-hydroxy(C₂ -C₇)alkyl; an ω-carboxy(C₁-C₇)alkyl; an ω-amino(C₂ -C₇)alkyl in which the amino group is free orsubstituted by one or two (C₁ -C₇)alkyls; R₈ is hydrogen or a (C₁-C₇)alkyl; R₉ is hydrogen, a (C₁ -C₇)alkyl; a (C₁ -C₇)alkylcarbonyl; agroup COAr; a pyridylcarbonyl; a group --CONR₁₄ R₂₄ ; or a group--CSNR₁₄ R₂₄ ; or else R₈ and R₉, together with the nitrogen atom towhich they are bonded, form a Δ3-pyrrolin-1-yl; R₁₁ and R₁₉ are eachindependently hydrogen; or a (C₁ -C₇)alkyl; R₁₃ is hydrogen; a (C₁-C₇)alkyl; a formyl; a (C₁ -C₇)alkylcarbonyl; a (C₁ -C₇)alkoxycarbonyl;R₁₄ is hydrogen or a (C₁ -C₇)alkyl; R₂₄ is hydrogen; a (C₁ -C₇)alkyl; a(C₁ -C₇)alkyl substituted by R₁₅ ; or a (C₃ -C₇)cycloalkyl; or R₁₄ andR₂₄, together with the nitrogen atom to which they are bonded, form apiperidine; R₁₅ is a group Ar; a pyridyl; a hydroxyl; a (C₁ -C₇)alkoxy;a group --NR₁₁ R₁₉ ; a carboxyl; or a (C₁ -C₇)alkoxycarbonyl; R₁₇ ishydrogen or a (C₁ -C₇)alkyl; R₁₈ is hydrogen; a (C₁ -C₈)alkyl; a (C₃-C₇)cycloalkyl which is unsubstituted or substituted by a (C₁ -C₄)alkyl;or else R₁₇ and R₁₈, together with the nitrogen atom to which they arebonded, form a heterocyclic radical selected from the group consistingof morpholin-4-yl, thiomorpholin-4-yl, azetidin-1-yl, piperazin-1-yl,piperid-1-yl and pyrrolidin-1-yl; Ar is a phenyl which is unsubstitutedor monosubstituted or polysubstituted by a substituent selected from ahalogen atom, a (C₁ -C₇)alkyl, a trifluoromethyl, a hydroxyl, a (C₁-C₇)alkoxy, a carboxyl, a (C₁ -C₇)alkoxycarbonyl, a (C₁-C₇)alkylcarbonyloxy, a nitro, a cyano, an amino, a (C₁ -C₇)alkylaminoand a (C₁ -C₇)dialkylamino, said substituents being identical ordifferent; m is 1, 2, 3 or 4, provided that when m is 2, 3 or 4 ech R₆independently represents a halogen, a (C₁ -C₇)alkyl or a (C₁ -C₇)alkoxy;p and q are each an integer, it being possible for their sum to varyfrom 3 to 6; X is oxygen or a group --NR₁₃ ;provided that at least oneof --CR₃ R₄, R₅ and R₆ contains one or more heterocyclic radicals; andits salts.
 9. A compound according to claim 1 of formula (I), in whichR₃ and R₄, together with the carbon to which they are bonded, form apiperidin-4 ring which is unsubstituted or substituted on the nitrogenby a (C₁ -C₇)alkyl; and its salts.
 10. A pharmaceutical compositioncontaining (i) an effective amount of a compound according to claim 1 ora pharmaceutically acceptable salt thereof, (ii) an effective amount ofanother active principle selected from the group consisting of aconverting enzyme inhibitor, an angiotensin II antagonist, a renininhibitor, a peripheral vasodilator, a calcium inhibitor, abeta-blocker, an alpha-1-blocker and a diuretic and (iii) suitableexcipients.
 11. A pharmaceutical composition containing (i) effectiveamounts of two compound according to claim 1 or pharmaceuticallyacceptable salts thereof, one being a specific V₁ receptor antagonistand the other being a specific V2 receptor antagonist and (ii) suitableexcipients.
 12. A pharmaceutical composition containing (i) effectiveamounts of two compound according to claim 1 or pharmaceuticallyacceptable salts thereof, one being a specific V₁ receptor antagonistand the other being a specific oxytocin antagonist and (ii) suitableexcipients.